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Registrar training talk
 

Registrar training talk

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Ali Could you e-mail me the web link. I have forgotten it. Also could we

Ali Could you e-mail me the web link. I have forgotten it. Also could we
talk about using its format to design diabetes web site. Thanks Mollie


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  • DISCUSSION This diagram demonstrates the GLP-1 effects in humans and the role these effects play in normal physiology. Upon the ingestion of food, plasma glucose levels increase postprandially. GLP-1 is secreted from intestinal L cells and provides a stimulus to the β -cells to release insulin in a glucose-dependent manner. When plasma glucose levels return to normal, the action of GLP-1 decreases 1 . GLP-1 also suppresses glucagon levels that are inappropriately elevated in patients with type 2 diabetes 1 . Lower glucagon levels leads to decreased hepatic glucose output 2 . In the stomach, GLP-1 slows the rate of gastric emptying, which reduces the rate at which meal-derived glucose appears in the circulation 3 . In the brain, GLP-1 promotes satiety and reduces appetite, which leads to a feeling of fullness and a reduction in food intake 4,5 . All these actions help maintain overall glucose homeostasis. 1 Nauck MA, et al. Diabetologia 1993;36:741–744 2 Larsson H, et al. Acta Physiol Scand 1997;160:413–422 3 Nauck MA, et al. Diabetologia 1996;39:1546–1553 4 Flint A, et al. J Clin Invest 1998;101:515–520 5 Zander et al. Lancet 2002;359:824–830.
  • DISCUSSION There is a sharp difference between the insulin response to oral glucose compared with the response to intravenous glucose. This difference in the insulin secretory response between administration of oral versus intravenous glucose is termed the incretin effect. Plasma glucose levels are shown in the left panel. The right-hand panel shows the insulin response as measured by C-peptide (a surrogate marker for insulin). On the left, the blue line demonstrates plasma glucose levels achieved in response to an oral glucose load. The blue line on the right indicates the corresponding insulin response. The orange lines demonstrate the plasma glucose and C-peptide responses to intravenous glucose. The difference is the incretin effect, indicated by the shaded area on the right. Subjects received glucose doses of 25, 50, or 100 g dissolved in a standard volume of 400 ml in a random order. The graph above demonstrates the response to a 50 g oral glucose load. BACKGROUND C-peptide is produced when proinsulin is split into insulin and C-peptide in response to a rise in plasma glucose, and therefore it acts as a surrogate marker for insulin production. Nauck MA, et al. J Clin Endocrinol Metab 1986;63:492–498.
  • DISCUSSION The β -cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with type 2 diabetes. Patients with diabetes exhibited a greater β -cell secretory response than control subjects, as indicated by higher insulin secretion levels, during the 180-minute course of intravenous glucose infusion. BACKGROUND Differences in insulin response to oral and intravenous glucose administration, which are attributed to factors other than glucose itself, describe the incretin effect; the incretin effect appears to be reduced in patients with type 2 diabetes. Measured insulin and C-peptide responses to a 50 g oral glucose load and an isoglycaemic intravenous infusion. Additionally, an attempt was made to correlate incretin effects to GIP responses. Insulin measurements are shown here. Plasma insulin responses were studied for 14 patients with type 2 diabetes in this study and 8 metabolically healthy control subjects. Nauck MA, et al. Diabetologia 1986;29:46–52
  • References 1. Victoza Summary of Product Characteristics. http://emc.medicines.org.uk/medicine/21986/SPC/Victoza+6+mg+ml+solution+for+injection+in+pre-filled+pen/ 2. Vilsbøll T, Hare, KJ, Bagger JO, Knop FK. Glucagon-like peptide-1 and diabetes treatment. International Diabetes Monitor 2009 ;21:1–7
  • DISCUSSION The objective was to test the hypothesis that the exenatide effect on glycaemic control was non-inferior to the insulin glargine effect, based on change in HbA 1c (exenatide– glargine) HbA 1c was measured at screening (Week -4), baseline (Week 0), Week 12, Week 26 (endpoint) and, if possible, at the time of discontinuation for those who dropped out of the study before completion at Week 26 Non-inferiority margin for the difference between treatments (exenatide minus insulin glargine) was defined as 0.4%. Outcome measurements: proportion of patients achieving HbA 1c <100mg/dL). This was not required for exenatide patients, since fixed dosing schedule was used STUDY BACKGROUND Multi-centre, randomised, open-label phase III clinical trial comparing the effects of exenatide and insulin glargine on glycaemic control over 26 weeks, as measured by reduction in HbA 1c , in patients with type 2 diabetes achieving inadequate glycaemic control using combination metformin and sulphonylurea therapy at maximally effective doses
  • DISCUSSION At endpoint, the average dose of insulin glargine was 25.0 IU/day (N = 244). 21.6% of insulin glargine patients, compared with 8.6% of exenatide patients, achieved a fasting glucose of <0.4% STUDY BACKGROUND Multi-centre, randomised, open-label phase III clinical trial comparing the effects of exenatide and insulin glargine on glycaemic control over 26 weeks, as measured by reduction in HbA 1c , in patients with type 2 diabetes achieving inadequate glycaemic control using combination metformin and sulphonylurea therapy at maximally effective doses HbA 1c was measured at screening (Week -4), baseline (Week 0), Week 12, Week 26 (endpoint) and, if possible, at the time of discontinuation for those who dropped out of the study before completion of Week 26
  • Exenatide reduced postprandial glucose excursions compared to insulin glargine. Insulin glargine-treated patients had lower pre-meal glucose levels but had higher postmeal glucose levels than exenatide-treated patients. Baseline fasting plasma glucose FPG profiles were similar between the 2 treatment groups: exenatide 10.2 mmol/L; insulin glargine 10.1 mmol/L.
  • DISCUSSION Insulin glargine patients gained weight throughout the trial period, while exenatide was associated with progressive reductions in weight Mean body weight was significantly different between the two treatments at 2 weeks, and this difference persisted throughout the study Adjusted mean change in body weight at endpoint was -2.3 kg for exenatide, +1.8 kg for insulin glargine Mean difference (exenatide - insulin glargine) was -4.1 kg, 95% CI for the difference -4.6 to -3.5 kg Baseline body weights were exenatide: 87.5 ± 16.9 kg and insulin glargine: 88.3 ± 17.9 kg STUDY BACKGROUND Multi-centre, randomised, open-label phase III clinical trial comparing the effects of exenatide and insulin glargine on glycaemic control over 26 weeks, as measured by reduction in HbA 1c , in patients with type 2 diabetes achieving inadequate glycaemic control using combination metformin and sulphonylurea therapy at maximally effective doses
  • This slide shows the phase 3 clinical trials undertaken to investigate the efficacy and tolerability of liraglutide added to oral antidiabetic drugs . The metformin add-on trial compared liraglutide with placebo and glimepiride in patients receiving metformin (1). The SU add-on trial compared liraglutide with placebo and rosiglitazone in patients receiving glimepiride (2). The metformin + TZD add-on trial compared liraglutide with placebo in patients receiving metformin plus rosiglitazone (3). The metformin + SU add-on trial compared liraglutide with placebo and insulin glargine in patients receiving metformin plus glimepiride (4). With its broad range of background therapies and the use of placebo and active comparators, the phase 3 clinical trial programme investigated liraglutide at several points in the T2D treatment pathway and gave comprehensive data on its clinical profile. References 1. Nauck M et al. Diabetes Care 2009;32:84–90 2. Marre M et al. Diabet Med 2009;26:268–278 3. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009; in press
  • The phase 3 clinical trial programme had broad entry criteria (1−4). The protocols included wash-out of prior oral therapies followed by forced titration of background treatments. Liraglutide could be administered at any time of the day, irrespective of meals, into the abdomen, thigh or upper arm. These three injection sites provide similar bioavailability of liraglutide (5). Patients were informed that it was preferable to administer liraglutide at the same time each day. Liraglutide was administered by forced titration to a maximum of 1.8 mg/day according to the trial protocols; dose reduction was not allowed. The trials were statistically powered to detect superiority of liraglutide over placebo and noninferiority versus active comparators. Tests for superiority of liraglutide over active comparators were also done. The change in HbA 1c from baseline was the primary endpoint for all phase 3 studies. Secondary endpoints included fasting plasma glucose (FPG), postprandial glucose (PPG) assessed as self-measured blood glucose after each meal, body weight, lipids, blood pressure (BP), hypoglycaemia, antibodies against liraglutide and surrogate markers of beta-cell function. References 1. Marre M et al. Diabet Med 2009;26:268–278 2. Nauck M et al. Diabetes Care 2009;32:84–90 3. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009; in press 5. Kapitza C et al. ADA 68th Scientific Sessions, San Francisco, USA, 6−10 June 2008 [Abstract No. 2146-PO]
  • This slide shows the percent change in HbA 1c for the overall treatment groups in the phase 3 clinical trial programme for liraglutide (the bars) and, within the bars, the percentages of patients reaching an HbA 1c level of <0.0001
  • This slide shows the changes in body weight from baseline with liraglutide, placebo and active comparators (1–4). Most trials demonstrated reductions in body weight of approximately 1–3 kg from baseline with liraglutide 1.2 or 1.8 mg/day. By contrast, glimepiride, rosiglitazone and insulin glargine were associated with weight gain. These results show that liraglutide produces weight loss in patients with T2D. Further analyses examined the reduction in body weight across categories of body mass index (BMI) at baseline (5). The results showed that in the metformin add-on and metformin + SU add-on trials, a reduction in body weight with liraglutide was seen irrespective of baseline body weight although it was greatest in patients with a high baseline BMI. The comparisons of liraglutide with placebo are shown in the table below (ns = not significant). References 1. Nauck M et al. Diabetes Care 2009;32:84−90 2. Marre M et al. Diabet Med 2009;26:268−278 3. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009, in press 5. Russell-Jones D et al. ADA 68th Scientific Sessions, San Francisco, USA, 6−10 June 2008 [Abstract No. 2147-P] Trial Change from baseline with placebo (kg) Liraglutide 1.2 mg vs placebo Liraglutide 1.8 mg vs placebo Met add-on (1) -1.5 p≤0.01 p≤0.01 SU add-on (2) -0.1 ns ns Met + TZD add-on (3) +0.6 p<0.0001 Met + SU add-on (4) -0.4 – P=0.0001
  • The phase 3 trials showed that liraglutide reduces systolic blood pressure (BP) (1 − 4). This slide shows the changes from baseline in systolic BP with liraglutide 1.2 or 1.8 mg/day and active comparators (there was no active comparator in the Met + TZD add-on trial [5]). In most studies the reduction with liraglutide was 2 − 3 mmHg but in the metformin + TZD add-on trial it was 6 − 7 mmHg. The reduction from baseline in systolic BP with liraglutide 1.2 or 1.8 mg/day was statistically significant compared with glimepiride (1) and with insulin glargine (4). Diastolic BP did not change significantly in these trials (1 − 4). The reductions in systolic BP seen with liraglutide occurred within 2 weeks and could not be explained by changes in body weight (5). The comparisons of liraglutide with placebo are shown in the table below (ns = not significant). References Nauck M et al. Diabetes Care 2009;32:84−90 2. Marre M et al. Diabet Med 2009;26:268−278 3. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009, in press 5. Colagiuri S et al. 44th Annual meeting of the European Association for the Study of Diabetes (EASD), 7−11 September 2008, Poster presentation P899 Trial Change from baseline with placebo (mmHg) Placebo vs liraglutide 1.2 mg Placebo vs liraglutide 1.8 mg Met add-on (1,2) -1.8 ns ns SU add-on (3,6) -2.3 ns ns Met + TZD add-on (4) -1.1 p<0.05 Met + SU add-on (5) -1.4 ns ns
  • References Buse J, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett J, Zychma M, Blonde L. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;374(9683):39-47. Buse J, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, Blonde L, Rosenstock J. Switching from twice-daily exenatide to once-daily liraglutide improves glycemic control in T2D on oral agents. Diabetes 2009; 58 (Suppl 1): A159.
  • HbA1c values at week 26 for full population were: Exenatide: 7.21% Liraglutide: 6.95% Estimated treatment difference: p<0.0001 (Buse et al., Lancet 2009) References Buse J, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, Blonde L, Rosenstock J. Switching from twice-daily exenatide to once-daily liraglutide improves glycemic control in T2D on oral agents. Presented at ADA 2009: 591-P. Buse J, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett J, Zychma M, Blonde L. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;374(9683):39-47.
  • Values at week 26 (start of extension) were: (Data on file, LEAD6ext/02, Novo Nordisk) Exenatide -> liraglutide: 7.2% Liraglutide -> liraglutide: 7.0% References Buse J, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, Blonde L, Rosenstock J. Switching from twice-daily exenatide to once-daily liraglutide improves glycemic control in T2D on oral agents. Diabetes 2009; 58 (Suppl 1): A159.
  • FPG values at week 26 for full population were: Exenatide: 8.64 mmol/L Liraglutide: 7.73 mmol/L Estimated treatment difference: p<0.0001 (Buse et al., Lancet 2009) References Buse J, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, Blonde L, Rosenstock J. Switching from twice-daily exenatide to once-daily liraglutide improves glycemic control in T2D on oral agents. Presented at ADA 2009: 591-P. Buse J, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett J, Zychma M, Blonde L. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;374(9683):39-47.
  • References Buse J, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett J, Zychma M, Blonde L. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;374(9683):39-47. Buse J, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, Blonde L, Rosenstock J. Switching from twice-daily exenatide to once-daily liraglutide improves glycemic control in T2D on oral agents. Diabetes 2009; 58 (Suppl 1): A159.
  • Case presentations to be used to discuss at end.
  • With exenatide, 6 kg wt loss and HbA1c fall to 7.3%

Registrar training talk Registrar training talk Presentation Transcript

  • NEW KIDS ON THE BLOCK Dr Mollie Donohoe Dr Amanda Stride 22 September 2009
    • What are GLP mimetics?
    • What do the studies show?
    • What are current NICE guidelines?
    • What are we doing in clinical practice?
  • Incretins
    • Incretins are hormones secreted by intestinal endocrine cells in response to nutrient intake 1
    • Incretins influence glucose homeostasis via multiple actions including glucose-dependent insulin secretion 2 , postprandial glucagon suppression and slowing of gastric emptying 3
    • Incretins were identified when it was observed that orally ingested glucose provoked a higher insulin response than comparable glucose administered intravenously 4
      • This is called the “incretin effect”
      • The incretin effect accounts for ~60% of total insulin release following a meal 4
    • 1Drucker DJ. Diabetes Care 2003;26:2929–2940; 2 Nauck MA, et al. Diabetologi a 1993;36:741–744 ; 3 Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Nauck M, et al. Diabetologia 1986;29:46–52.
  • GLP-1 effects in humans understanding the natural role of incretins Adapted from 1 Nauck MA, et al. Diabetologi a 1993;36:741–744; 2 Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3 Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4 Flint A, et al. J Clin Invest 1998;101:515–520; 5 Zander et al. Lancet 2002;359:824–830. GLP-1 secreted upon the ingestion of food 1.  - cell: Enhances glucose-dependent insulin secretion in the pancreas 1 3.Liver: reduces hepatic glucose output 2 2. α - cell: Suppresses postprandial glucagon secretion 1 4.Stomach: slows the rate of gastric emptying 3 5.Brain: Promotes satiety and reduces appetite 4,5
  • Incretin Effect
    • Augmentation of glucose-stimulated insulin secretion by intestinally derived peptides, which are released in presence of glucose or nutrients in the gut
  • The incretin effect β -cell response to oral vs IV glucose Mean (SE); * P  0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:492–498. Plasma glucose values converted to mmol/L from mg/dL using conversion factor of 0.0555; C-peptide values converted to nmol/L from ng/mL using conversion factor 0.333. Plasma glucose (mmol/L) Time (min) C-peptide (nmol/L) Oral glucose (50 g) Isoglycaemic intravenous (IV) glucose 12 2 0 Crossover of healthy subjects (N = 6) 0 60 120 180 4 6 8 10 Plasma glucose (mmol/L) Time (min) 0 60 120 180 0.0 0.5 1.0 1.5 2.0 * * * * * * * Incretin Effect C-peptide (nmol/L)
  • The incretin effect is reduced in patients with type 2 diabetes 0 20 40 60 80 Insulin (mU/L) 0 30 60 90 120 150 180 Time (min) 0 20 40 60 80 0 30 60 90 120 150 180 Time (min) * P ≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia 1986;29:46–52. Patients with type 2 diabetes Control subjects Intravenous Glucose Oral Glucose Insulin (mU/L) * * * * * * * * * *
  • The New Kids: Exenatide and Liraglutide
    • Incretin mimetics – exhibits gluco regulating actions similar to GLP-1.
    • Resistant to degradation by dipeptidypeptidase.
    • Exenatide approved by FDA as adjunctive Rx in Type 2 on metformin/SU or both not achieving adequate control of BG.
    • Liraglutide – once daily human GLP analogue.
  • Homology to native GLP-1 with two GLP-1 agonists 97% amino acid homology to human GLP-1 peptide 1 53% amino acid homology to human GLP-1 peptide 2 Study duration: Liraglutide 26 weeks; exenatide 30 weeks. 1 Victoza SmPC, 2009 2 Vilsbøll et al. International Diabetes Monitor 2009;21:1-7
  •  
  • What do studies show?
  • Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes
    • Primary Objective
    • To compare effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes that is suboptimally controlled with metformin (MET) and sulphonylurea (SU)
    • 26-week treatment, BD fixed dose exenatide versus OD insulin glargine (titrate to fasting blood glucose level <5.6 mmol/L)
    • Primary endpoint: Change in HbA 1c from baseline
    • ITT sample: N = 549 randomised patients with  1 post-baseline measurement
    Heine R, et al. Ann Intern Med 2005;143:559–569.
  • Change in HbA 1c over time, ITT population Time (weeks) 0 12 26 0 6.5 HbA 1c (%) Insulin glargine, mean dose at endpoint = 25.0 U/day (N = 260) Exenatide, 10 μ g (N = 275) ITT population: exenatide (N = 275) insulin glargine (N = 260), Mean ± SD shown Heine R, et al. Ann Intern Med 2005;143:559–569. 7.0 7.5 8.0 8.5
  • Exenatide Reduced Postprandial Glucose Excursions Blood Glucose (mmol/L) 6 8 10 12 14 Baseline Week 26 6 8 10 12 14 Baseline Week 26 Exenatide Insulin Glargine Fasting Pre-midday meal Pre-evening meal 3 AM Post-evening meal Post-midday meal Post-morning meal Fasting Pre-evening meal 3 AM Post-evening meal Post-midday meal Post-morning meal Pre-midday meal ITT sample; Mean ± SE shown. Heine RJ, et al . Ann Intern Med . 2005;143:559-569.
  • Change in body weight over time, ITT population Exenatide (N = 275) Insulin Glargine (N = 260) ITT population: exenatide (N = 275) insulin glargine (N = 260), Mean ± SD shown; * P < 0.0001, exenatide versus insulin glargine at same time point Heine R, et al. Ann Intern Med 2005;143:559–569. + 1.8 kg - 2.3 kg Time (weeks) Change in body weight (kg) 0 2 4 8 12 18 26 -3 -2 -1 0 1 2 * * * * * *
  • Safety and tolerability
    • Exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance of <30ml/min).
    • Not recommended for patients with severe gastrointestinal disease.
    • There was an increased risk of hypoglycaemia with sulphonylurea.
      • To reduce the risk of hypoglycaemia, reduction of dose of sulphonylurea should be considered.
    • Nausea was the most commonly reported adverse event ( > 5%) reported in phase II placebo-controlled studies.
    • Most episodes were mild to moderate and decreased over time in most patients.
  • Liraglutide phase 3 programme 1. Nauck M et al. Diabetes Care 2009;32:84–90 2. Marre M et al. Diabet Med 2009;26:268–278 3. Zinman B et al. Diabetes Care 2009;Epub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009, in press Comb = Oral combination therapy; Glim = glimepiride; Met = metformin; Mono = Oral monotherapy; Rosi = rosiglitazone; SU = sulphonylurea; TZD = thiazolidinedione (glitazone) Early in treatment pathway Later in treatment pathway Trial Met add-on 1 Lead 2 SU add-on 2 Lead 1 Met + TZD add-on 3 Lead4 Met + SU add-on 4 Lead 5 Background regimen Met 2 g Glim 4 mg Met 2 g + Rosi 8 mg Met 2 g + Glim 4 mg Comparators Glim 4 mg Placebo Rosi 4 mg Placebo Placebo Insulin glargine Placebo
    • Liraglutide administration: s.c. once daily, any time of day, irrespective of meals
    • Liraglutide injected into upper arm, abdomen or thigh, using a prefilled pen
    • Forced titration 0.6 mg  1.2 mg  1.8 mg according to protocol; dose reduction not allowed
    • Trials were powered for superiority vs placebo and non inferiority vs. active comparators
    • Primary endpoint: change in HbA 1c from baseline
    • Secondary endpoints included other measures of glucose control, weight, tolerability and beta-cell function
    1. Marre M et al. Diabet Med 2009;26:268–278 2. Nauck M et al. Diabetes Care 2009;32:84–90 3. Zinman B et al. Diabetes Care 2009;Epub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009, in press Liraglutide phase 3 programme: Design
  • Met = metformin; SU = sulphonylurea; TZD = thiazolidinedione (glitazone) Liraglutide phase 3 programme: Change in HbA 1c 1. Nauck M et al. Diabetes Care 2009;32:84–90 2. Marre M et al. Diabet Med 2009;26:268–278 3. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009, in press 44% 58% 54% 35% 42% 22% 42% 36% 35% p<0.0001 p=0.00139 % reaching ADA target (HbA 1c <7.0%) Met + SU add-on 4 SU add-on 2 Met add-on 1 Met + TZD add-on 3 -1.0 -1.0 -1.0 -1.08 -1.13 -0.44 -1.5 -1.5 -1.33 -1.09 Change in HbA 1c from baseline (%) -1.6 -1.4 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0 p<0.0001 44% 52% 54% 58% 42% 35% 22% 35% 36% 42% Rosiglitazone Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride Placebo Glargine -0.5 28% +0.2
  • Effects of liraglutide on body weight 1. Nauck M et al. Diabetes Care 2009;32:84–90 2. Marre M et al. Diabet Med 2009;26:268–278 3. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009, in press -2.8 -2.6 +1.0 p<0.0001 +0.3 +2.1 -0.2 p<0.0001 SU* add-on 2 Met add-on 1 Met + TZD add-on 3 Met + SU add-on 4 -2.0 -1.0 +0.6 -1.8 +1.62 p<0.0001 Met = metformin; SU = sulphonylurea; TZD = thiazolidinedione (glitazone) *Patients were taken off metformin before the trial – this may explain that weight loss was not observed 2 Rosiglitazone Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride Placebo Glargine Change in body weight from baseline (kg) -4 -3 -2 -1 0 1 2 3 p<0.0001 p<0.0001
  • -2.3 0.4 -2.8 p=0.0467 p=0.0128 -2.8 -2.6 -0.9 -6.7 -4.0 0.5 p=0.0001 Met add-on 1 SU add-on 2 Met + TZD add-on 3 Met +SU add-on 4 Met = metformin; ns = not significant; SU = sulphonylurea; TZD = thiazolidinedione (glitazone) 1. Nauck M et al. Diabetes Care 2009;32:84 − 90 2. Marre M et al. Diabet Med 2009;26(3):268 − 278 3. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March 4. Russell-Jones D et al. Diabetologia 2009, in press Change in SBP from baseline (mmHg) Effect of liraglutide on systolic blood pressure -5.6 -6 -5 -4 -3 -2 -1 0 1 p=ns p=ns -1.1 Rosiglitazone Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride Placebo Glargine
  • Exenatide v Liraglutide
    • What evidence is there?
  • Design of LEAD-6 and its extension study Liraglutide (n=200) 1.8 mg OD 14 weeks Liraglutide (n=186) 1.8 mg OD 12 weeks 1.2 mg OD 1 week 0.6 mg OD 1 week BID: twice daily; OD: once daily; BMI: body mass index 1 Buse et al. Lancet 2009;374(9683):39-47 2 Buse et al. Diabetes 2009;58 (Suppl 1):A159 and poster UK/LR/0709/0306 Date of Preparation July 2009 Adults 18–80 years with type 2 diabetes HbA 1c : 7.0-11.0% BMI ≤45 kg/m 2 Randomised, open-label, parallel-group study at 132 sites in Europe and the USA Liraglutide (n = 233) 0.6 mg OD 1 week 1.2 mg OD 1 week 1.8 mg OD 24 weeks Metformin and/or SU continued at pre-study dose Exenatide (n = 231) 5  g BID 4 weeks 10  g BID 22 weeks Screening 26 weeks 1 Extension: 14 weeks 2
  • Reduction in HbA 1c – core and extension phases Liraglutide Exenatide Liraglutide  liraglutide Exenatide  l iraglutide Time (weeks) ADA HbA 1c target Data for weeks 0–26 are only for patients that participated in the LEAD-6 extension phase *** Estimated treatment difference in changes for full population p <0.0001 7.21% 6.95% *** p <0.0001 Adapted from Buse et al. , poster presented at ADA 2009: 591-P UK/LR/0709/0306 Date of Preparation July 2009 Exenatide group switched to liraglutide (week 26)
  • Extension phase: Further HbA 1c reduction after switching from exenatide p <0.0001 Exenatide  liraglutide Liraglutide  liraglutide Adapted from Buse et al. Diabetes 2009;58 (Suppl 1):A159 UK/LR/0709/0306 Date of Preparation July 2009
  • Reduction in FPG – core and extension phases Liraglutide Exenatide Liraglutide  liraglutide Exenatide  liraglutide Time (weeks) *** Estimated treatment difference in changes for full population p <0.0001 8.64 7.73 *** p <0.0001 Data for weeks 0–26 are only for patients that participated in the LEAD-6 extension phase Adapted from Buse et al. , poster presented at ADA 2009: 591-P UK/LR/0709/0306 Date of Preparation July 2009 Exenatide group switched to liraglutide (week 26)
  • Both treatments lowered body weight Mean (2 SE) Estimated treatment difference in changes for full population NS 0 Liraglutide Exenatide Time (weeks) Liraglutide  liraglutide Exenatide  liraglutide Data for weeks 0–26 are only for patients that participated in the LEAD-6 extension phase Adapted from data on file (LEAD 6 ext/04), Novo Nordisk UK/LR/0709/0306 Date of Preparation July 2009 Exenatide group switched to liraglutide (week 26)
  • Proportion of subjects experiencing nausea Proportion of subjects (%) Time (weeks) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 10 8 6 4 2 0 12 14 18 20 16 Data are number (%) of patients exposed to treatment (safety population) 1 Buse et al. Lancet 2009;374(9683):39-47 *** p <0.0001 for treatment differences *** UK/LR/0709/0306 Date of Preparation July 2009 Exenatide 10 μ g BID Liraglutide 1.8 mg OD
  • Head-to-Head: liraglutide vs exenatide
    • In summary,
    • GLP-1 analogues are effective in lowering glycaemia
    • Liraglutide showed superior glycaemic-lowering ability, in regards to HbA 1c and FPG, compared with exenatide
    • Patients switching from exenatide to liraglutide achieved further improvements without compromising tolerability in:
      • HbA 1c
      • FPG
      • Weight
      • Beta-cell function
    Buse et al. Lancet 2009;374(9683):39-47 Buse et al. Diabetes 2009;58 (Suppl 1):A159 UK/LR/0709/0306 Date of Preparation July 2009
  • Current Guidelines
  • HbA1c > 6.5% after lifestyle measures Met Intensify Regimen Met + SU Insulin + Met + SU Intensify Regimen Start Insulin Met + SU + exenatide (BMI > 35kg/m 2 and problems with high body weight or insulin not appropriate or weight loss advantageous Or Met + SU + DPP-4 * Or Met + SU + TZD * *if significant risk of hypoglycaemia Rapid-acting insulin Met + TZD or Met + DPP-4 (if significant risk of hypoglycaemia) SU + TZD or SU + DPP-4 (if significant risk of hypoglycaemia) SU HbA1c > 6.5% HbA1c > 6.5% HbA1c > 7.5% HbA1c > 7.5% HbA1c > 7.5% HbA1c > 675% HbA1c > 7.5% HbA1c > 7.5% NICE recommendations for the management of hyperglycaemia in patients with type 2 diabetes. Continuous lines indicate ‘usual’ or ‘well-validated; regimens; dashed lines indicate ‘alternative or ‘less well validated’ options . Key: BMI = body mass index; DPP-4 = dipeptidyl peptidase-4 inhibitor; GLP-1 = glucagon-like peptide 1; HbA1c = glycated haemoglobin A1c; Met = metformin; SU =sulphonylurea; TZD = thiazolidinedione/glitazone
  • NICE guidelines 2008 Type 2 Diabetes Starting Exenatide
    • BMI >35 in those of European descent (adjusted accordingly for other ethnic groups)
    • Specific psychological, biochemical or physical problems arising from high body weight
    • HbA1c greater than or equal to 7.5% with conventional oral agents after a trial of metformin and sulphonylurea
    • Would otherwise be starting other high cost medication e.g. thiazolidinedione or insulin
  • NICE guidelines 2008 Type 2 Diabetes Continuation of Exenatide
    • Greater than or equal to 1% reduction in HbA1c at 6 months
    • Weight loss greater that 5% at one year
  • Exeter Guidelines
    • Individualised dietary and lifestyle education is the mainstay of therapy and should be tried for a period of 3 months before initialising drug therapy.
    • If patient <45 yrs or BMI <25 consider referral to secondary care for investigation of other aetiology
    Add isophane insulin nocte or bd Metformin commenced 500mg od and titrate to max tolerated dose (if GIT symptoms try starting at 125mg od) Add gliclazide 80mg od and titrate to max 160mg bd as required Add pioglitazone 30mg titrating to 45mg Add DPP-4 inhibitor Sitagliptin 5 -10mg od Add GLP agonist Exenatide 5mcg -10 mcg sc bd or Or In patients with strong reasons for avoiding insulin (eg vocational driving licence) HbA1c >6.5% HbA1c >7% Step 1 Time scales or Step 2 Step 3 3 - 6/12 3 - 6/12 3 - 6/12   HbA1c >7.5% STEPPED APPROACH TO TREATMENT OF TYPE 2 DIABETES (All targets should be individualised according to hypo risk and expected microvascular benefit)
  • Annual costs of drugs lowering BS
    • Metformin 850mg tds £37
    • Gliclazide 160mg bd £123
    • Rosi 8 mg od £660
    • Pio 45 mg od £480
    • Repaglinide 16mg daily £389
    • Exenatide 5/10mg bd £890
    • Liraglutide 1.2mg £921
    • Liraglutide 1.8mg £1413
    • Sitagliptin 100mg od £434
    • Rimonobant 20mg od £719
    • Insulin Glargine 25u/day £237
    • Insulatard 25u/day £133
    • Orlistat £400
  • What are we doing in clinical practice?
  • Exeter experience
    • DSN keeping record of all exenatide starts
    • 88 pts to date
    • 1 on liraglutide
    • Audit by Angus and Pam
  • Changes in weight & HbA1c
  • Changes in weight (kg) over time
  • Changes in HbA1c over time
  • Case presentations
    • Any from the floor?
    • Any comments about your experience with exenatide or liraglutide?
  • Case presentation 1 AS
    • 54 year old lady, EG
    • T2DM diagnosed 2004
    • Hyperchol
    • Hypertension
    • NAFLD
    • Obesity
    • Fibromyalgia and wheel chair bound
    • On metformin 2g, glipizide 5mg, simvastatin 80mg, fenofibrate 67mg bd
  • Case 1 cont
    • HbA1c 10.8%
    • Chol 7.2, TG 2.89
    • BP 184/64
    • Does not want any treatment that will cause her to put on weight.
    • What next?
  • Case 1 cont
    • Risk factor control
      • Simvastatin to atorvastatin
      • Add BFZ and amlodipine if necessary
      • Altered timing of OHAs due to SEs
    • HbA1C 9.2%
    • BP 168/92
    • Chol 6.8
    • What next?
  • Case 1 cont
    • Amlodipine added
    • Atorvastatin increased
    • Exenatide
    • CBGs fell from 20 to 10. Hypo symptoms so SU stopped
    • Over course of next 5 months lots of stopping and starting of all BP and chol meds
    • But HbA1c 6.6%
  • Case 2 AS
    • 70 yr old man
    • T2DM on metformin, gliclazide and pio.
    • Pio stopped due to fliud retention with increase in HbA1c.
    • Therefore insulin added but SU stopped with rise in HbA1C to 12.0%
    • Reintroduction of gliclazide lead to fall in HbA1c to 9.3% but weight gain
    • What next?