new treatments in diabetes

1. New treatments in Diabetes

3. What are incretins?

4. The �Incretin� effect

5. Incretins Peptides secreted by the intestinal mucosa in response to food intake Glucagon-like peptide-1 (GLP-1) Glucose-dependent insulinotrophic polypeptide (GIP)

6. Physiological effects of incretins ? prandial insulin secretion ? glucagon secretion ? Acid secretion and GI motility (? gastric emptying ? satiety and ? food intake ? � cell protection ? Cardiovascular effects

7. Abnormalities associated with T2D

8. Incretin effect after oral glucose was diminished in type 2 diabetes6

9. GLP-1 in vivo

10. Strategies for harnessing the therapeutic potential of GLP-1 Agents that mimic the actions of GLP-1 (incretin mimetics) Novel peptides that mimic some of the glucoregulatory actions of GLP-1 Exenatide DPP-IV�resistant GLP-1 derivatives Examples: GLP-1 analogues, albumin bound GLP-1 (Liraglutide) Agents that prolong the activity of endogenous GLP-1 DPP-IV Inhibitors

11. Exenatide - pharmacology Synthetic equivalent of exendin-4 Peptide found in the saliva of the Gila monster

12. Exenatide - pharmacology 53% homology with human GLP-1 Similar binding affinity to GLP-1 receptor Resistant to DPP-4 inactivation Administered by s/c injection

13. Exenatide � phase 3 studies 3 studies in patients on OHAs MFN alone (n=336) SU alone (n=377) MFN+SU (n=733) 30 week, double-blind RCT Adults, T2D, baseline FPG<13.3, HbA1c 7.1-11.0%, BMI 27-45, age 22-77

14. Study Design Phase 3 Clinical Studies DISCUSSION The three AMIGOs were randomized, double-blind, placebo-controlled, multi-centre trials. Patients were randomized to one of four treatment arms following a 4-week lead-in period with 0.02 mL placebo injection: 5 �g of exenatide for the duration of the study 5 �g of exenatide for the next 4 weeks followed by 10 �g exenatide for the remainder of the 30-week study A 0.02 mL placebo injection for the duration of the study A 0.02 mL placebo injection for the next 4 weeks followed by a 0.04 mL placebo injection for the remainder of the 30-week study BACKGROUND Patients were instructed to continue taking their oral diabetes medications, with exenatide added as adjunct therapy to the existing drug regimens. Exenatide was self-administered by patients as subcutaneous BID 15 minutes before the morning and evening meals. Both exenatide arms began with 5 �g exenatide for 4 weeks to minimize nausea, and placebo groups were combined for analyses. Participants could terminate the study under the following conditions: HbA1c up 1.5% from baseline or HbA1c >11.5% at Week 18 or 24 or Fasting glucose >240 mg/dL (lab test) or Fasting glucose >260 mg/dL (finger stick) for 2+ weeks DISCUSSION The three AMIGOs were randomized, double-blind, placebo-controlled, multi-centre trials. Patients were randomized to one of four treatment arms following a 4-week lead-in period with 0.02 mL placebo injection: 5 �g of exenatide for the duration of the study 5 �g of exenatide for the next 4 weeks followed by 10 �g exenatide for the remainder of the 30-week study A 0.02 mL placebo injection for the duration of the study A 0.02 mL placebo injection for the next 4 weeks followed by a 0.04 mL placebo injection for the remainder of the 30-week study BACKGROUND Patients were instructed to continue taking their oral diabetes medications, with exenatide added as adjunct therapy to the existing drug regimens. Exenatide was self-administered by patients as subcutaneous BID 15 minutes before the morning and evening meals. Both exenatide arms began with 5 �g exenatide for 4 weeks to minimize nausea, and placebo groups were combined for analyses. Participants could terminate the study under the following conditions: HbA1c up 1.5% from baseline or HbA1c >11.5% at Week 18 or 24 or Fasting glucose >240 mg/dL (lab test) or Fasting glucose >260 mg/dL (finger stick) for 2+ weeks

15. DISCUSSION At Week 30, compared to placebo, significant HbA1c reductions were seen in the 5 �g and 10 �g exenatide treatment arms in all 3 studies. The percentage reduction in HbA1c in the 10 �g exenatide arm was greater than in the 5 �g exenatide arm. Exenatide was associated with reduced HbA1c independent of background oral therapy (MET and/or SFU). BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of MET, SFU, or MET + SFU. Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed in the United States. This slide presents combined data. Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomized to placebo (PBO), 5 �g exenatide BID, or 10 �g exenatide BID, N = 1446. All subjects also continued current medication. MET study: PBO n = 113, baseline HbA1c = 8.2%; exenatide 5 �g n = 110, baseline HbA1c = 8.3%; exenatide 10 �g n = 113, baseline HbA1c = 8.2% SFU study: PBO n = 123, baseline HbA1c = 8.7%; exenatide 5 �g n = 125, baseline HbA1c = 8.5%; exenatide 10 �g n = 129, baseline HbA1c = 8.6% MET + SFU study: PBO n = 247, baseline HbA1c = 8.5%; exenatide 5 �g n = 245, baseline HbA1c = 8.5%; exenatide 10 �g n = 241, baseline HbA1c = 8.5% The Last Observation Carried Forward (LOCF) method was applied to the data. Exenatide was associated with reduced HbA1c independent of disease duration.DISCUSSION At Week 30, compared to placebo, significant HbA1c reductions were seen in the 5 �g and 10 �g exenatide treatment arms in all 3 studies. The percentage reduction in HbA1c in the 10 �g exenatide arm was greater than in the 5 �g exenatide arm. Exenatide was associated with reduced HbA1c independent of background oral therapy (MET and/or SFU). BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of MET, SFU, or MET + SFU. Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed in the United States. This slide presents combined data. Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomized to placebo (PBO), 5 �g exenatide BID, or 10 �g exenatide BID, N = 1446. All subjects also continued current medication. MET study: PBO n = 113, baseline HbA1c = 8.2%; exenatide 5 �g n = 110, baseline HbA1c = 8.3%; exenatide 10 �g n = 113, baseline HbA1c = 8.2% SFU study: PBO n = 123, baseline HbA1c = 8.7%; exenatide 5 �g n = 125, baseline HbA1c = 8.5%; exenatide 10 �g n = 129, baseline HbA1c = 8.6% MET + SFU study: PBO n = 247, baseline HbA1c = 8.5%; exenatide 5 �g n = 245, baseline HbA1c = 8.5%; exenatide 10 �g n = 241, baseline HbA1c = 8.5% The Last Observation Carried Forward (LOCF) method was applied to the data. Exenatide was associated with reduced HbA1c independent of disease duration.

16. Exenatide reduced body weight over 30 Weeks DISCUSSION In all three studies, progressive reductions in body weight were seen at Week 30 in both the 5 �g and 10 �g exenatide treatment arms. The greatest weight loss was demonstrated in the 10 �g exenatide arm of the MET study. BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of MET, a SFU, or MET + SFU. Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed. This slide presents combined data. Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomized to PBO, 5 �g exenatide BID, or 10 �g exenatide BID, N = 1446. All subjects also continued current medication. MET study: PBO n = 113, baseline weight 100 kg; exenatide 5 �g n = 110, baseline weight 100 kg; exenatide 10 �g n = 113, baseline weight 101 kg SFU study: PBO n = 123, baseline weight 99 kg; exenatide 5 �g n = 125, baseline weight 95 kg; exenatide 10 �g n = 129, baseline weight 95 kg MET + SFU study: PBO n = 247, baseline weight 99 kg; exenatide 5 �g n = 245, baseline weight 97 kg; exenatide 10 �g n = 241, baseline weight 98 kg The LOCF method was applied to the data. Weight change was a secondary endpoint. No additional diet and exercise counseling was provided to the study patients in the clinical trials. DISCUSSION In all three studies, progressive reductions in body weight were seen at Week 30 in both the 5 �g and 10 �g exenatide treatment arms. The greatest weight loss was demonstrated in the 10 �g exenatide arm of the MET study. BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of MET, a SFU, or MET + SFU. Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed. This slide presents combined data. Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomized to PBO, 5 �g exenatide BID, or 10 �g exenatide BID, N = 1446. All subjects also continued current medication. MET study: PBO n = 113, baseline weight 100 kg; exenatide 5 �g n = 110, baseline weight 100 kg; exenatide 10 �g n = 113, baseline weight 101 kg SFU study: PBO n = 123, baseline weight 99 kg; exenatide 5 �g n = 125, baseline weight 95 kg; exenatide 10 �g n = 129, baseline weight 95 kg MET + SFU study: PBO n = 247, baseline weight 99 kg; exenatide 5 �g n = 245, baseline weight 97 kg; exenatide 10 �g n = 241, baseline weight 98 kg The LOCF method was applied to the data. Weight change was a secondary endpoint. No additional diet and exercise counseling was provided to the study patients in the clinical trials.

17. Common adverse events DISCUSSION In assessing combined results from all three Phase 3 clinical trials, the most common adverse events were nausea and hypoglycaemia. BACKGROUND Three 30-week, double-blind, Phase 3 studies have been completed in the United States: Patients with type 2 diabetes randomized to placebo, 5 �g exenatide BID, or 10 �g exenatide twice daily (BID) with metformin (MET), ITT N = 336 Patients with type 2 diabetes randomized to placebo, 5 �g exenatide BID, or 10 �g exenatide BID with a sulphonylurea (SFU), ITT N = 377 Patients with type 2 diabetes randomized to placebo, 5 �g exenatide BID, or 10 �g exenatide BID with MET and SFU, ITT N = 733 In general, nausea was mild-to-moderate and had a minimal to moderate effect on daily activities. The incidence of nausea decreased over time. Likewise, hypoglycaemia was mostly mild-to-moderate in intensity. One severe hypoglycaemic event occurred in a patient receiving SFU (within the 5 �g exenatide treatment arm). Exenatide did not increase the incidence of hypoglycaemia when combined with MET. Mild-to-moderate hypoglycaemia incidence increased in groups where exenatide was added to a SFU. Hypoglycaemia was defined as follows: Mild-to-moderate hypoglycaemia: subject reported symptoms consistent with hypoglycaemia that may have been documented by a plasma glucose concentration value (<3.33 mmol/L). Severe hypoglycaemia: subject required the assistance of another person to obtain treatment for their hypoglycaemia; treatment included oral carbohydrate, intravenous glucose, or intramuscular glucagon. DISCUSSION In assessing combined results from all three Phase 3 clinical trials, the most common adverse events were nausea and hypoglycaemia. BACKGROUND Three 30-week, double-blind, Phase 3 studies have been completed in the United States: Patients with type 2 diabetes randomized to placebo, 5 �g exenatide BID, or 10 �g exenatide twice daily (BID) with metformin (MET), ITT N = 336 Patients with type 2 diabetes randomized to placebo, 5 �g exenatide BID, or 10 �g exenatide BID with a sulphonylurea (SFU), ITT N = 377 Patients with type 2 diabetes randomized to placebo, 5 �g exenatide BID, or 10 �g exenatide BID with MET and SFU, ITT N = 733 In general, nausea was mild-to-moderate and had a minimal to moderate effect on daily activities. The incidence of nausea decreased over time. Likewise, hypoglycaemia was mostly mild-to-moderate in intensity. One severe hypoglycaemic event occurred in a patient receiving SFU (within the 5 �g exenatide treatment arm). Exenatide did not increase the incidence of hypoglycaemia when combined with MET. Mild-to-moderate hypoglycaemia incidence increased in groups where exenatide was added to a SFU. Hypoglycaemia was defined as follows: Mild-to-moderate hypoglycaemia: subject reported symptoms consistent with hypoglycaemia that may have been documented by a plasma glucose concentration value (<3.33 mmol/L). Severe hypoglycaemia: subject required the assistance of another person to obtain treatment for their hypoglycaemia; treatment included oral carbohydrate, intravenous glucose, or intramuscular glucagon.

18. Open-Label Extension: Exenatide Sustained HbA1c Reductions Over 82 Weeks DISCUSSION In this open-label extension study (OLEs), upon receiving exenatide, the placebo group showed an immediate decrease in HbA1c similar to that observed with exenatide treatment in the first 30 weeks; the decrease in HbA1c was maintained throughout 82 weeks. Mean HbA1c reductions from baseline were very similar at 82 weeks (at least -1.1%) for all three original study treatment groups. BACKGROUND Of the 1446 subjects randomized to the three 30-week, double-blinded, placebo-controlled trials (3 AMIGOs), 1125 completed treatment and were eligible for enrollment into the OLEs. Of the 1125 subjects, 977 (87%) enrolled in the OLEs. At the time of this data analysis, 795 had completed treatment through 52 weeks, and 393 had completed treatment through 82 weeks. 82-week data (30 weeks from the placebo-controlled, double-blind study and 52 weeks from the OLE) are shown for 393 patients (placebo, n = 128; 5 �g exenatide BID, n = 128; 10 �g exenatide BID, n = 137). Using the ITT and LOCF analysis methods, the ITT population (N = 977) demonstrated HbA1c and weight reductions consistent with the 82-week completer population shown here. For patients receiving 10 �g exenatide BID for 82 weeks, 51% achieved an HbA1c of ?7% at 82 weeks.DISCUSSION In this open-label extension study (OLEs), upon receiving exenatide, the placebo group showed an immediate decrease in HbA1c similar to that observed with exenatide treatment in the first 30 weeks; the decrease in HbA1c was maintained throughout 82 weeks. Mean HbA1c reductions from baseline were very similar at 82 weeks (at least -1.1%) for all three original study treatment groups. BACKGROUND Of the 1446 subjects randomized to the three 30-week, double-blinded, placebo-controlled trials (3 AMIGOs), 1125 completed treatment and were eligible for enrollment into the OLEs. Of the 1125 subjects, 977 (87%) enrolled in the OLEs. At the time of this data analysis, 795 had completed treatment through 52 weeks, and 393 had completed treatment through 82 weeks. 82-week data (30 weeks from the placebo-controlled, double-blind study and 52 weeks from the OLE) are shown for 393 patients (placebo, n = 128; 5 �g exenatide BID, n = 128; 10 �g exenatide BID, n = 137). Using the ITT and LOCF analysis methods, the ITT population (N = 977) demonstrated HbA1c and weight reductions consistent with the 82-week completer population shown here. For patients receiving 10 �g exenatide BID for 82 weeks, 51% achieved an HbA1c of ?7% at 82 weeks.

19. Open-Label Extension: Exenatide Progressively Reduced Body Weight Over 82 Weeks DISCUSSION In this open-label extension study, upon receiving exenatide, the placebo group demonstrated an immediate decrease in weight similar to that observed with exenatide treatment in the first 30 weeks. Mean body weight reductions mediated by exenatide during the first 30 weeks were sustained and appeared to be progressive through 82 weeks. BACKGROUND Of the 1446 subjects randomized to the three 30-week, double-blinded, placebo-controlled trials (3 AMIGOs), 1125 completed and were eligible for enrollment into the OLEs. Of the 1125 subjects, 977 (87%) enrolled into the OLEs. At the time of this data analysis, 795 had completed treatment through 52 weeks and 393 had completed treatment through 82 weeks. 82-week data (30 weeks from the placebo-controlled, double-blind study and 52 weeks from the OLE) are shown for 393 patients (placebo, n = 128; 5 �g exenatide BID, n = 128; 10 �g exenatide BID, n = 137). Using the ITT and LOCF analysis methods, the ITT population (N = 977) demonstrated HbA1c and weight reductions consistent with the 82-week completer population shown here. Reductions in body weight occurred without any additional diet and exercise counseling. DISCUSSION In this open-label extension study, upon receiving exenatide, the placebo group demonstrated an immediate decrease in weight similar to that observed with exenatide treatment in the first 30 weeks. Mean body weight reductions mediated by exenatide during the first 30 weeks were sustained and appeared to be progressive through 82 weeks. BACKGROUND Of the 1446 subjects randomized to the three 30-week, double-blinded, placebo-controlled trials (3 AMIGOs), 1125 completed and were eligible for enrollment into the OLEs. Of the 1125 subjects, 977 (87%) enrolled into the OLEs. At the time of this data analysis, 795 had completed treatment through 52 weeks and 393 had completed treatment through 82 weeks. 82-week data (30 weeks from the placebo-controlled, double-blind study and 52 weeks from the OLE) are shown for 393 patients (placebo, n = 128; 5 �g exenatide BID, n = 128; 10 �g exenatide BID, n = 137). Using the ITT and LOCF analysis methods, the ITT population (N = 977) demonstrated HbA1c and weight reductions consistent with the 82-week completer population shown here. Reductions in body weight occurred without any additional diet and exercise counseling.

20. Open-Label Extension Disposition: 2-Year Exenatide Exposure DISCUSSION Of the 1446 subjects enrolled, 1125 completed the placebo-controlled trials and 977 of those entered the open-label extension studies (OLE). Of the 977 subjects enrolled, 974 were ITT and 3 were withdrawn prior to first dose of Exenatide. The 3 withdrawn subjects were included in the above 151 subjects that did not enter the OLE. Of those 974 subjects, 668 were randomized to exenatide treatment during the placebo-controlled trials. The other 306 were randomized to placebo and were not included in this analysis due to <104 weeks of exposure to exenatide. 354 (includes 5 subjects from an additional study site) of the 668 subjects randomized to exenatide had the chance to complete 104 weeks of exenatide treatment by the time of this data analysis. Of those 354 subjects: 195 subjects (55%) completed 104 weeks of exenatide treatment. 159 subjects (45%) withdrew: 14% due to withdrawal of consent 8% due to adverse events 3.5% due to nausea while all other adverse events that lead to withdrawal were reported by one subject each. 4% due to loss of glucose control 19% due to other reasons including lost to follow-up, investigator decision, protocol violation, missing, and administrative. DISCUSSION Of the 1446 subjects enrolled, 1125 completed the placebo-controlled trials and 977 of those entered the open-label extension studies (OLE). Of the 977 subjects enrolled, 974 were ITT and 3 were withdrawn prior to first dose of Exenatide. The 3 withdrawn subjects were included in the above 151 subjects that did not enter the OLE. Of those 974 subjects, 668 were randomized to exenatide treatment during the placebo-controlled trials. The other 306 were randomized to placebo and were not included in this analysis due to <104 weeks of exposure to exenatide. 354 (includes 5 subjects from an additional study site) of the 668 subjects randomized to exenatide had the chance to complete 104 weeks of exenatide treatment by the time of this data analysis. Of those 354 subjects: 195 subjects (55%) completed 104 weeks of exenatide treatment. 159 subjects (45%) withdrew: 14% due to withdrawal of consent 8% due to adverse events 3.5% due to nausea while all other adverse events that lead to withdrawal were reported by one subject each. 4% due to loss of glucose control 19% due to other reasons including lost to follow-up, investigator decision, protocol violation, missing, and administrative.

21. Exenatide/Insulin Glargine Comparator Trial: Study Design 26-week treatment, BD fixed-dose exenatide vs OD insulin glargine titration Primary endpoint: Change in HbA1c Intention-to-treat sample: N = 549 randomized patients with =1 post-baseline measurement DISCUSSION Patients were randomized to two study arms. One arm received exenatide 5 �g BID for 4 weeks, then the dose was increased to 10 �g BID for the remainder of the study. The second arm received insulin glargine at an initial dose of 10 Units/day (U/d), then in self-titrated doses using a fixed-dose algorithm. BACKGROUND This randomized, open-label, Phase 3 clinical trial compared the effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes not achieving adequate glycaemic control with combination MET and SFU therapy at maximally effective doses. Glycaemic control was defined as a reduction in HbA1c level. Patients were 30 to 75 years of age and treated with stable and maximally effective doses of MET and SFU for at least 3 months prior to screening. General inclusion criteria included a screening HbA1c of 7.0% to 10.0% and a BMI >25 kg/m2 and <45 kg/m2. Second arm began at an initial dose of 10 Units/day, then self-titrated to achieve a fasting blood glucose target level of <100 mg/dL (5.6 mmol/L) on daily glucose monitoring. DISCUSSION Patients were randomized to two study arms. One arm received exenatide 5 �g BID for 4 weeks, then the dose was increased to 10 �g BID for the remainder of the study. The second arm received insulin glargine at an initial dose of 10 Units/day (U/d), then in self-titrated doses using a fixed-dose algorithm. BACKGROUND This randomized, open-label, Phase 3 clinical trial compared the effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes not achieving adequate glycaemic control with combination MET and SFU therapy at maximally effective doses. Glycaemic control was defined as a reduction in HbA1c level. Patients were 30 to 75 years of age and treated with stable and maximally effective doses of MET and SFU for at least 3 months prior to screening. General inclusion criteria included a screening HbA1c of 7.0% to 10.0% and a BMI >25 kg/m2 and <45 kg/m2. Second arm began at an initial dose of 10 Units/day, then self-titrated to achieve a fasting blood glucose target level of <100 mg/dL (5.6 mmol/L) on daily glucose monitoring.

22. Achieved Equivalent Reductions in HbA1c DISCUSSION HbA1c was significantly reduced from baseline at Week 26 in both treatment arms. A similar percentage of patients (46% of patients in the exenatide group and 48% of patients in the insulin glargine group) reached an HbA1c goal of <7% for each treatment arm. BACKGROUND This randomized, open-label, Phase 3 clinical trial compared the effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes not achieving adequate glycaemic control with combination MET and SFU therapy at maximally effective doses. Glycaemic control was defined as a reduction in HbA1c level. Patients were randomized to two study arms. One arm received exenatide 5 �g BID for 4 weeks; the dose was increased to 10 �g twice daily for the remainder of the study. A second arm received insulin glargine at an initial dose of 10 Units/day (U/d), then in self-titrated doses using a fixed-dose algorithm to achieve a fasting blood glucose target level of <100 mg/dL (5.6 mmol/L) on daily glucose monitoring. Patients were 30 to 75 years of age and treated with stable and maximally effective doses of MET and SFU for at least 3 months prior to screening. General inclusion criteria included a screening HbA1c of 7.0% to 10.0% and a BMI >25 kg/m2 and <45 kg/m2. The proportion of patients achieving HbA1c <7% was a secondary endpoint. DISCUSSION HbA1c was significantly reduced from baseline at Week 26 in both treatment arms. A similar percentage of patients (46% of patients in the exenatide group and 48% of patients in the insulin glargine group) reached an HbA1c goal of <7% for each treatment arm. BACKGROUND This randomized, open-label, Phase 3 clinical trial compared the effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes not achieving adequate glycaemic control with combination MET and SFU therapy at maximally effective doses. Glycaemic control was defined as a reduction in HbA1c level. Patients were randomized to two study arms. One arm received exenatide 5 �g BID for 4 weeks; the dose was increased to 10 �g twice daily for the remainder of the study. A second arm received insulin glargine at an initial dose of 10 Units/day (U/d), then in self-titrated doses using a fixed-dose algorithm to achieve a fasting blood glucose target level of <100 mg/dL (5.6 mmol/L) on daily glucose monitoring. Patients were 30 to 75 years of age and treated with stable and maximally effective doses of MET and SFU for at least 3 months prior to screening. General inclusion criteria included a screening HbA1c of 7.0% to 10.0% and a BMI >25 kg/m2 and <45 kg/m2. The proportion of patients achieving HbA1c <7% was a secondary endpoint.

23. Exenatide Resulted in Progressive Weight Reductions 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 as early as 2 weeks, and this difference persisted throughout the study. Adjusted mean change in body weight at endpoint was -5.1 � 0.4 lbs for exenatide, +4.0 � 0.4 lbs for insulin glargine. BACKGROUND This randomized, open-label, Phase 3 clinical trial compared the effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes not achieving adequate glycaemic control with combination MET and SFU therapy at maximally effective doses. Patients were randomized to two study arms. One arm received exenatide 5 �g BID for 4 weeks; the dose was increased to 10 �g BID for the remainder of the study. A second arm received insulin glargine at an initial dose of 10 Units/day (U/d), then in self-titrated doses using a fixed-dose algorithm to achieve a fasting blood glucose target level of <100 mg/dL (5.6 mmol/L) on daily glucose monitoring. Patients were 30 to 75 years of age and treated with stable and maximally effective doses of MET and SFU for at least 3 months prior to screening. General inclusion criteria included a screening HbA1c of 7.0% to 10.0% and a BMI >25 kg/m2 and <45 kg/m2. Mean difference in weight change (exenatide - insulin glargine) was -9.0 lbs, CI -10.1, -7.7 lbs. Baseline body weights were: exenatide 87.5 � 16.9 kg and insulin glargine 88.3 � 17.9 kg. Controlling hyperglycaemia without causing weight gain in patients with type 2 diabetes is an important therapeutic benefit of incretin mimetics. 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 as early as 2 weeks, and this difference persisted throughout the study. Adjusted mean change in body weight at endpoint was -5.1 � 0.4 lbs for exenatide, +4.0 � 0.4 lbs for insulin glargine. BACKGROUND This randomized, open-label, Phase 3 clinical trial compared the effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes not achieving adequate glycaemic control with combination MET and SFU therapy at maximally effective doses. Patients were randomized to two study arms. One arm received exenatide 5 �g BID for 4 weeks; the dose was increased to 10 �g BID for the remainder of the study. A second arm received insulin glargine at an initial dose of 10 Units/day (U/d), then in self-titrated doses using a fixed-dose algorithm to achieve a fasting blood glucose target level of <100 mg/dL (5.6 mmol/L) on daily glucose monitoring. Patients were 30 to 75 years of age and treated with stable and maximally effective doses of MET and SFU for at least 3 months prior to screening. General inclusion criteria included a screening HbA1c of 7.0% to 10.0% and a BMI >25 kg/m2 and <45 kg/m2. Mean difference in weight change (exenatide - insulin glargine) was -9.0 lbs, CI -10.1, -7.7 lbs. Baseline body weights were: exenatide 87.5 � 16.9 kg and insulin glargine 88.3 � 17.9 kg. Controlling hyperglycaemia without causing weight gain in patients with type 2 diabetes is an important therapeutic benefit of incretin mimetics.

24. Exenatide - pharmaceutical Now available for treatment of T2D (Byetta, Lilly) Licensed as adjunct to MFN, SU or both Given as BD s/c injection � prefilled pen 5mcg bd for 1st month, then 10mcg ongoing �68.25 per month / �818.00 per year Has not yet been �NICEd�

25. Exenatide in our area RUH Drug Policy Group have recently granted �red� status Consultant prescription only Collecting audit data on all patients started Due for review Feb 2008 (aiming for amber status) Currently 4 patients receiving it

26. ADA/EASD guidelines (2006) Guidelines support an early, intensive approach to the management of Type 2 diabetes. The American Diabetes Association and the European Association for the Study of Diabetes (ADA�EASD) have produced a consensus algorithm for the management of hyperglycaemia in Type 2 diabetes. This emphasises the value of early and intensive treatment and proposes that an HbA1c ? 7% �should serve as a call to action to initiate or change therapy�. Treatment should aim to bring glycaemic control �as near to normal as possible� (e.g. HbA1c < 6%) where practical, appropriate and free of significant hypoglycaemia or at a minimum decrease it to < 7% for most patients. The structure of the algorithm and selection of therapies takes into account the long-term progressive nature of Type 2 diabetes. The algorithm emphasises: Achievement and maintenance of normal glycaemic goals Initial therapy with lifestyle intervention and metformin Rapid addition of medications, and transition to new regimens, when target glycaemic goals are not achieved or sustained Early addition of insulin therapy in patients who do not meet targets. Link to next slide: Let�s summarise what we have learned Reference Nathan DM et al. Diabetes Care 2006; 29: 1963�1972.Guidelines support an early, intensive approach to the management of Type 2 diabetes. The American Diabetes Association and the European Association for the Study of Diabetes (ADA�EASD) have produced a consensus algorithm for the management of hyperglycaemia in Type 2 diabetes. This emphasises the value of early and intensive treatment and proposes that an HbA1c ? 7% �should serve as a call to action to initiate or change therapy�. Treatment should aim to bring glycaemic control �as near to normal as possible� (e.g. HbA1c < 6%) where practical, appropriate and free of significant hypoglycaemia or at a minimum decrease it to < 7% for most patients. The structure of the algorithm and selection of therapies takes into account the long-term progressive nature of Type 2 diabetes. The algorithm emphasises: Achievement and maintenance of normal glycaemic goals Initial therapy with lifestyle intervention and metformin Rapid addition of medications, and transition to new regimens, when target glycaemic goals are not achieved or sustained Early addition of insulin therapy in patients who do not meet targets. Link to next slide: Let�s summarise what we have learned Reference Nathan DM et al. Diabetes Care 2006; 29: 1963�1972.


28. Patients to consider for Exenatide BMI>35 Contraindication to glitazone Bar to starting insulin (eg HGV driver)

29. The future for Exenatide Combination with other agents (already licensed in US) Exenatide LAR Islet cell transplants

30. Liraglutide GLP-1 agonist (2aa different) Novo product uses detemir technology � binds to albumin OD s/c dose (t1/2 10-18 hrs) Earlier in development Optimal dose yet to be defined Phase 3 studies about to be published Aiming for launch mid 2008

31. Strategies for harnessing the therapeutic potential of GLP-1 Agents that mimic the actions of GLP-1 (incretin mimetics) Novel peptides that mimic some of the glucoregulatory actions of GLP-1 Exenatide DPP-IV�resistant GLP-1 derivatives GLP-1 analogues, albumin bound GLP-1 (Liraglutide) Agents that prolong the activity of endogenous GLP-1 DPP-IV Inhibitors

32. DPP-IV inhibitors Sitagliptin (Januvia, MSD) Launched May 2007 License: Add on to MFN or TZD Dose: 100mg od (not recommended if Cr clearance <50ml/min) Cost �33.26 per 28 days Vildagliptin (Galvus, Novartis) Filed for approval in US and EU Aiming for UK launch end 2007

33. Sitagliptin � phase 3 studies 3 studies in patients on OHAs MFN alone (n=701) Pioglitazone alone (n=353) Comparison with SU as add-on to MFN (n=1172) 24/52 week, double-blind RCT T2D, baseline FPG 9.5, HbA1c 8%, BMI 30, age 54

34. 24-week Add-on Therapy to Metformin StudyMean change in HbA1c over time

35. 24-week Add-on Therapy to Pioglitazone Study Mean values in HbA1c over time

36. 52-week Sitagliptin vs Sulphonylureaa Add-on Therapy to Metformin Study

37. Sitagliptin provided weight reduction (vs weight gain) and a lower incidence of hypoglycaemia

38. Safety and tolerability of DPP-IV GI s/e less prominent than for GLP-1 analogues No significant hypos Weight neutral Possible increase in infections Nasopharyngitis RR 1.2 UTI RR 1.5



41. Comparison of incretin mimetics

42. NB No long term safety data No outcome data

43. Topics to be covered Incretin-based treatments Inhaled insulin Glucophage SR

44. Inhaled insulin Exubera�(Pfizer) licensed in UK T2 not adequately controlled on OHAs and requiring insulin T1 in addition to intermediate insulin in whom potential benefits outweigh safety concerns Available for prescription since August 2006 Dry powder recombinant human insulin Unique device for delivery of the drug to the alveoli

45. Exubera� inhaler NOT like asthma devices - around 6� long Significant training required Insulin release unit should be replaced every 2/52 � on prescription

46. Dosing Blisters contain 1mg or 3mg inhaled insulin Equivalent to 3U or 8U regular insulin 3x1mg does not equal 1x3mg Starting dose: Wt(kg) x 0.15mg/kg = mg/day Divide into 3 equal doses pre meals Titrate in 1mg increments

47. Contraindications Smoking (must have stopped for at least 6/12) � increased risk of hypoglycaemia Asthma � poorly controlled/severe Severe COPD Limited experience in CCF � not recommended

48. Side effects Cough Hypoglycaemia Decline in FEV1 and DLCO Stable after 6/12 Reverses on withdrawal of inhaled insulin FEV1 monitoring required Development of insulin antibodies � no apparent clinical significance in trials to date

49. Trial data 7 trials in T1, 2 in T2 T1 compared to regular human insulin (actrapid), no head to head with analogue or CSII Set up to show non-inferiority � no significant differences if efficacy Patient satisfaction higher ADA � 2yr data sustained efficacy, no further deterioration in lung function

50. NICE guidance Issued Dec 2006 Not recommended for routine treatment of T1 or T2 Consider in patients with poor glycaemic control despite all efforts with conventional Rx plus Needle phobia meeting DSM IV criteria or Severe injection site problems Only continue beyond 6/12 if sustained improvement in glycaemic control deemed to be clinically relevant to reducing complications Only to be started by specialist centre as part of prospective observational study

51. My approach in clinic Dispel the inhaler myth Not a quick fix � still on basal bolus Not as rapid-acting as analogue insulin � may worsen hypoglycaemia Lack of dosing flexibility Concern re pulmonary s/e Smoking

52. Other products in development

53. Topics to be covered Incretin-based treatments Inhaled insulin Glucophage SR

54. Glucophage SR Once daily dosing Improved compliance Improved GI tolerability Regimen Start 500mg od with main meal or the total dose of conventional MFN currently being taken Increment every 10 days to 2g total Cost �3.20 - �12.80 per 28 days Due to be considered by BCAP shortly

55. Glucophage SR � superior GI tolerability to standard MFN

new treatments in diabetes

new treatments in diabetes

Presentation Transcript

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