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London Medicines Evaluation Network Overview: Glucagon-Like Peptide-1 receptor analogues The first stop for professional medicines advice 1

London Medicines Evaluation Network Overview: Glucagon-Like Peptide-1 receptor analogues Licensing(L)/NICE Approval(N) Dual Therapy Triple Therapy Renal Impairment Drug Name Available Preparations Route Dosing Frequency Cost per year (as per BNF March 2016) *1 Monotherapy Metformin Sulphonylurea Pioglitazone Basal Insulin L L L L L NICE L NICE L L L L L L Metformin & Sulphonylurea Sulphonylurea & Pioglitazone Metformin & Pioglitazone Basal Insulin + Metformin Basal Insulin + Sulphonylurea Basal Insulin + Basal Insulin + metformin + NICE Evidence Base <30ml/min or End Stage Renal Disease 30-50ml/min 50-80ml/min Liver Impairment Drug-specific cautions Impact on weight loss Hypoglycaemic events Exenatide Liraglutide Lixisenatide Dulaglutide Albiglutide Standard Release Byetta Modified Release Bydureon Victoza Insulin degludec Xultophy Lyxumia Trulicity Eperzan SUBCUTANEOUS Twice Daily 830.25 In adults type 2 diabetes, only offer a GLP- Once 1 analogue in Weekly 953.68 combination insulin specialist care Once advice and Daily 954.84 * * ongoing support * * * * * * * Once Daily from a consultantled Range from 387.43 to multidisciplinary team 1,937.14 * * * * * * * * * * * * Once Daily 704.82 * * * * * * * * * * * Once Weekly 952.25 * * * * * * * * * Not addressed Once Weekly 923.00 * * * * * * * * * * * Not addressed 2nd intensification therapy ** **If triple therapy metformin and 2 other oral drugs is not effective, not tolerated or contraindicated, combination therapy metformin, sulfonylurea + a GLP-1 analogue can be considered if HbA1C >7.5%, BMI 35kg/m 2 OR BMI <35kg/m 2 and insulin therapy would have significant occupational implications/weight loss would benefit other significant obesity related comorbidities. See Overleaf and Appendix 1 Not recommended Dose escalation from 5 to 10mcg should proceed conservatively Not recommended - limited clinical experience No dose adjustment required No dose adjustment required No dose adjustment required No dose adjustment required No dose adjustment required Use intensified glucose monitoring and subsequent dose adjustment on an individual level No dose adjustment required No dose adjustment required No dose adjustment required in mild to moderate impairment. Use is not recommended in severe impairment Not recommended due to limited evidence base No dose adjustment required No dose adjustment required No dose adjustment required Nil specific to exenatide Thyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in clinical trials in particular in patients preexisting thyroid disease and liraglutide should therefore be used caution. Nil specific to lixisenatide Nil specific to dulaglutide Nil specific to albiglutide According to NICE's meta-analysis, in general combinations of 3 non-insulin drugs were generally associated weight gain except for combinations GLP-1 agonists (evidence base for exenatide/liraglutide+ metformin+sulphoylur ea considered), which showed a trend for weight loss when compared to metformin+nph insulin. According to NICE's meta-analysis, three noninsulin based drug combinations (including 2nd intensification GLP-1 analogues) were generally associated less hypoglycaemic events compared to the metformin-nph insulin combination. Not addressed by NICE guidance Key Licensed for use, no cautions and no dose adjustments required Byetta *1 Calculation of Annual Cost Based on a dose of 10mcg exenatide twice daily Use caution as risk of hypoglycaemia is increased, therefore manufacturers advise to consider dose reduction of /basal insulin when GLP-1 analogue added to reduce this risk Mentioned in section 4.2 of SPC although no data specifically supporting these combinations. Not Licensed for use Not addressed by NICE License states "in combination other glucose-lowering medicinal products including basal insulin, when these, together diet and exercise, do not provide adequate glycaemic control." These combinations are those for which supporting data are available in the product information, although the decision to prescribe is left to * the discretion of the clinician. Trulicity License states "in combination other glucose-lowering medicinal products including basal insulin, when these, together diet and exercise, do not provide adequate glycaemic control." These combinations are those for which supporting data are not available in the product information, although the decision to prescribe is * left to the discretion of the clinician. Eperzan Bydureon Victoza Xultophy Lyxumia Based on dose of 2mg exenatide once a week Based on liraglutide dose of 1.2mg once a day Annual cost ranges from 387.43 for a daily dose of 10 dose-steps (10 units insulin degludec and 0.36 mg liraglutide) to 1937.14 for a daily dose of 50 dose-steps (50 units insulin degludec and 1.8 mg liraglutide). Based on lixisenatide dose of 20mcg once daily Based on dulaglutide dose of either 0.75mg/week (monotherapy) or 1.5mg/week (combination therapy) Based on albiglutide dose of either 30mg (starting dose) or 50mg once a week (maximum dose) 2

Brief summary of evidence base for GLP-1 Analogues in diabetes Drug Preparation Brief Summary of pivotal studies Exenatide Standard Release Byetta Modified Release Bydureon The safety and efficacy of standard release exenatide was investigated in eight key studies (six placebo-controlled, two active-comparator controlled) which included 3,067 patients type 2 diabetes 1-5. Six randomised comparator-controlled studies were conducted to evaluate the effects of Bydureon on glycaemic control a range of background therapies. A total of 3,225 patients were included in the studies 6-11. Six phase III trials (five double-blind and one open label) were conducted to evaluate the effects of liraglutide on glycaemic control a range of background therapies. A total of 3,968 patients were included in these studies 12-17. Liraglutide Lixisenatide Dulaglutide Albiglutide Victoza Insulin degludec Xultophy Lyxumia Trulicity Eperzan Additional trials were conducted liraglutide that included 1,901 patients in four unblinded randomised controlled trials 12. Of these studies, one key phase 3b study which reports the use of liraglutide as add on therapy to basal insulin in 177 patients has been included 18. A recent study (published June 2016) comparing once daily liraglutide vs. lixisenatide as add-on therapy to metformin in 404 patients was also included 19. The safety and efficacy of Xultophy has been established based on three published randomised controlled phase III studies including 2,630 patients Type 2 diabetes on a range of background therapies 20-23. One unpublished study including 435 patients on background therapy a ± metformin was also included as it has been highlighted in the summary of product characteristics for Xultophy 20. The clinical efficacy and safety of lixisenatide were evaluated in nine randomised double-blind, placebo-controlled clinical studies including 4,509 patients type 2 diabetes 24-32. Efficacy of lixisenatide was also assessed in one pivotal randomised, open-label, active-controlled study (versus exenatide) (in total 634 patients randomised to either lixisenatide or exenatide) 33. A recent study (published June 2016) comparing once daily liraglutide vs. lixisenatide as add-on therapy to metformin in 404 patients was also included 19. The safety and efficacy of dulaglutide was evaluated in six randomised, controlled, phase III trials involving 5,171 patients type 2 diabetes 34-39. All six studies compared dulaglutide to an active comparator, and one of the studies was both active and placebo controlled. The safety and efficacy of albiglutide was evaluated in eight active and placebo-controlled phase III clinical trials including a total of 4,840 patients type 2 diabetes. Studies evaluated the use of albiglutide 30 mg and 50 mg once weekly, allowing for optional titration of albiglutide from 30 mg to 50 mg once weekly in 5 of the 8 studies 40. 3

Appendix 1: Summary of primary endpoint data for pivotal studies of GLP-1 Analogues in diabetes Drug Preparation License Evidence Base Exenatide Byetta Standard Release Summary The safety and efficacy of standard release exenatide was investigated in eight key studies (six placebocontrolled, two active-comparator controlled) which included 3,067 patients type 2 diabetes 1-5. metformin Triple-blind placebo-controlled study (n=336) found in patients treated on background therapy metformin, exenatide at doses of 5mcg and 10mcg twice daily was superior to placebo in reduction of HbA1c from baseline at 30 weeks (-0.40%, -0.78%, and +0.08%, respectively [p<0.002]) 1. Triple-blind placebo-controlled study (n=377) found in patients treated on background therapy s, exenatide at doses of 5 mcg and 10 mcg twice daily was superior to placebo in the reduction of HbA1c from baseline at 30 weeks (-0.46%, -0.86%, and +0.12%, respectively [p<0.001]) 2. metformin + metformin + basal insulin basal insulin + metformin basal insulin + basal insulin + metformin + Double-blind placebo-controlled study (n=733) found in patients treated on background therapy metformin+, exenatide at doses of 5mcg and 10mcg twice daily was superior to placebo in the reduction of HbA1c from baseline at 30 weeks (-0.6%, -0.8%, and +0.12%, respectively [p<0.0001]) 3. Two placebo-controlled studies (one of 16-week duration, and one of 26-week duration 233 and 165 participants, respectively) adding exenatide to existing thiazolidinedione treatment ± metformin. Of the exenatide patients in both studies (n=232), 12% were treated a thiazolidenedione and exenatide and 82% were treated thiazolidinedione treatment, metformin and exenatide. Both studies showed statistically significant reductions in HbA1c from baseline compared to placebo (-0.7% vs. +0.1% in the 16-week study and -0.8% vs. -0.1% in the 26-week study for exenatide vs. placebo, respectively) 4. Three studies measuring the efficacy of exenatide in combination basal insulin were conducted: The first was a placebo-controlled study (n=259) in patients on insulin glargine (alone [15%], metformin [70%], [3%] or metformin+ [12%]). At the end of a 30-week period, exenatide demonstrated a statistically significant reduction in the HbA1c compared to placebo (-1.74% vs. -1.04%, p<0.001) 5. The second was a 24-week study (n=337), in which either insulin lispro protamine suspension or insulin glargine were added to existing therapy of Byetta and metformin, metformin and or metformin and (exact patient characteristics not available) (1.2% vs. 1.4%, respectively) 4. The third was a 30-week open-label, active comparator-controlled non-inferiority study (n=627) in patients on a background of optimised basal insulin glargine and metformin. Non-inferiority in reduction of HbA1c of Byetta to titrated insulin lispro was demonstrated (-1.1% reduction in HbA1c from baseline [at 30 weeks] for both insulin glargine and metformin) 4. 4

Drug Preparation License Evidence Base Exenatide Bydureon Modified Release Summary Six randomised comparator-controlled phase III studies were conducted to evaluate the effects of Bydureon on glycaemic control a range of background therapies. A total of 3,225 patients were included in the studies 6-11. In addition to the studies described below, a 26-week RCT (n=820) in drug-naive patients found that Bydureon as monotherapy was non-inferior to metformin (2000mg/day) but not to (45mg/day) and was superior to sitagliptin (100mg/day) in change in HbA1c from baseline at 26 weeks (-1.53%, -1.48%, -1.63%, and -1.15%, respectively). This study was designed to test superiority if non-inferioity was established 6. metformin metformin + Metformin alone: One 26-week randomised double blind superiority study (n=491) found for patients on background therapy metformin, Bydureon was superior to both sitagliptin and in reduction of HbA1c from baseline at 26 weeks (- 1.5%, -0.9%, and -1.2%, respectively [p<0.0001 for exenatide vs. sitagliptin and p=0.0165 for exenatide vs. ]) 7. Various background therapies: One 25-week open-label randomised superiority study (n=456) found for patients on background treatment either metformin only (70%) and metformin+ (30%), that change in HbA1c from baseline at 26 weeks was greater in patients taking Bydureon compared to those taking insulin glargine (-1.5% vs. -1.3%, respectively[p=0.017]) 8. A 30-week open-label randomised non-inferiority study (n=295) in patients naïve to drug therapy (15%), or on pharmacological treatment (metformin (36%), (5%) or thiazolidenedione (3%), metformin+ (28%) or metformin+thiazolidenedione (9%)) found, at 30 weeks Bydureon was non-inferior to Byetta in reduction of HbA1c from baseline (-1.9% vs. -1.5% respectively [p=0.0023]). Baseline characteristics for previous therapy only documented for 284 patients (96%) 9. A 24-week open-label comparator-controlled study (n=252) in patients on a variety of background medications (19% drug naive, 47% taking one oral antidiabetic, and 35% taking multiple oral antidiabetics; 75% of study population were taking metformin, 29% were taking s, and 14% were taking thiazolidenediones) found at 24-weeks Bydureon was superior to Byetta in reduction of HbA1c from baseline (-1.6% vs. -0.9%, p<0.0001). This study was designed the power to detect non-inferiority, but superiority hypotheses were also specified in the protocol and tested for if non-inferiority was achieved 10. A 26-week open-label non-inferiority study (n=911) found that Bydureon did not meet the specified non-inferiority criteria vs. liraglutide (1.8mg daily) for reduction in HbA1c from baseline although both led to improvements in glycaemic control (-1.28% vs. -1.48%). Patients included in this study were on a range of background therapies; metformin + (60.6%), metformin alone (31.4%), alone (4%), metformin+ (3.7%), metformin++ (0.2%), alone (0.1%) 11. 5

Drug Preparation License Evidence Base Liraglutide Victoza Summary Six phase III trials (five double-blind and one open label) were conducted to evaluate the effects of liraglutide on glycaemic control a range of background therapies. A total of 3,968 patients were included in these studies 12-17. Additional trials were conducted liraglutide that included 1,901 patients in four unblinded randomised controlled trials 12. Of these studies, one key phase 3b study which reports the use of liraglutide as add on therapy to basal insulin in 177 patients has been included 18. A recent study (published June 2016) comparing once daily liraglutide vs. lixisenatide as add-on therapy to metformin in 404 patients was also included 19. Monotherapy Double-blind randomised controlled trial (n=745) found liraglutide monotherapy for 52 weeks resulted in statistically superior reductions in HbA1c vs. glimepiride 8mg/day (-0.84% for 1.2mg liraglutide, -1.14% for 1.8mg liraglutide vs. -0.51% for glimepiride, metformin metformin + metformin + basal insulin p<0.01 and p<0.0001, respectively) 12. Double blind randomised placebo and active-controlled trial (n=845) found at 26 weeks in patients on background metformin therapy, liraglutide (1.2mg and 1.8mg) were superior to placebo in change in HbA1c from baseline (p<0.0001) and non-inferior to active comparator glimepiride (-0.97%, -1.00%, +0.09%, and -0.98% for liraglutide 1.2mg, liraglutide 1.8mg, placebo, and glimepiride 4mg/day, respectively [p<0.0001 for both superiority and non-inferiority]) 12-13. Open-label, randomised, parallel group study (n=404) found at 26 weeks in patients on background metformin therapy, 1.8mg liraglutide reduced HbA1c more than 20µg lixisenatide (difference -0.62%, p<0.0001). Body weight reductions were similar and both treatments were well tolerated, low risk of hypoglycaemia 19. Double blind randomised placebo and active-controlled trial (n=808) found at 26 weeks when added on to glimepiride, liraglutide (1.2mg and 1.8mg) was superior both placebo and rosiglitazone 4mg/day in change in HbA1c from baseline (-1.08%, -1.13%, +0.23%, -0.44% for liraglutide 1.2mg, liraglutide 1.8mg, placebo, and rosiglitazone 4mg/day, respectively [p<0.0001 for all].) In this study, superiority to placebo was tested first then non-inferiority to rosiglitazone, and then finally superiority of liraglutide to rosglitazone 12,14. Double blind randomised controlled trial (n=576) where liraglutide 1.8mg was added on to metformin 2000mg/day + glimepiride 4mg/day found liraglutide was superior for change in HbA1c to both placebo and active comparator insulin glargine (-1.33%, -0.24%, and -1.09%, [p<0.0001 vs. placebo and p<0.01 vs. insulin glargine]).this study was designed power to detect both non-inferiority and superiority, first superiority of liraglutide vs. insulin glargine was proven, followed by non-inferiority of liraglutide to insulin glargine, and if proven lead to testing of superiority of liraglutide to insulin glargine 12,15. Open label non-inferiority randomised controlled study (n=464) comparing the efficacy and safety of liraglutide 1.8 mg once daily and exenatide 10 mcg twice daily in patients inadequately controlled on therapy metformin alone (27%), alone (10%) or both (63%), liraglutide was statistically superior to exenatide treatment in reducing HbA1c after 26 weeks (-1.12% vs -0.79%, p<0.0001). The investigators first established non-inferiority and then tested for superiority in this study 12,16. Double blind randomised controlled trial (n=530) found at 26 weeks when added on to metformin 2000mg/day + rosiglitazone 4mg/day, liraglutide 1.2mg and 1.8mg were superior to placebo in the reduction of HbA1c from baseline (-1.48%, -1.48%, and - 0.54%, respectively [p<0.0001]) 17. In a 104-week clinical trial, 57% of patients type 2 diabetes treated insulin degludec in combination metformin achieved a target HbA1c <7% and the remaining patients continued in a 26-week phase 3b open label trial (n=177) and were randomised to add liraglutide or a single dose of insulin aspart ( the largest meal). In the insulin degludec + liraglutide arm, the insulin dose was reduced by 20% in order to minimize the risk of hypoglycaemia. Addition of liraglutide resulted in a statistically significantly greater reduction of HbA1c (-0.73% for liraglutide vs -0.40% for insulin aspart, p=0.0024) 12,18. 6

Drug Preparation License Evidence Base Liraglutide Xultophy Summary The safety and efficacy of Xultophy has been established based on three published randomised controlled phase III insulin degludec studies including 2,630 patients Type 2 diabetes on a range of background therapies. One unpublished study including 435 patients on background therapy a ± metformin was also included as it has been highlighted in the summary of product characteristics for Xultophy 20-23. In addition to the studies described below, a non-inferiority study (n=557) found that in patients uncontrolled Type 2 diabetes on insulin glargine+metformin, Xultophy was non-inferior to insulin glargine+metformin up-titration of insulin in reduction of HbA1c (-1.81% vs. -1.13%, respectively [p<0.001 for non-inferiority]) 21. metformin metformin + metformin + Open-label randomised controlled study (n=1660) found that at 26 weeks Xultophy was non-inferior to insulin degludec and superior to liraglutide in reduction of HbA1c from baseline at 26 weeks (change in HbA1c-1.91%, -1.44% and - 1.28%, respectively [p<0.0001]) in patients on background therapy of metformin ± (17% on both metformin and ) 22. Double-blind randomised controlled study (n=413) found that at 26 weeks, Xultophy was superior to insulin degludec alone in patients on background therapy metformin in reduction of HbA1c (-1.9% vs. -0.9%, respectively [p<0.0001]) 23. One 26-week randomised, placebo-controlled, double-blind, treat-to-target trial (n=435 patients) found that the change in HbA1c from baseline was significantly greater Xultophy compared to placebo (-1.45% vs. -0.46%, p<0.0001) in patients on background therapy ± metformin. (unpublished data, cited in product information 20 ) 7

Drug Preparation License Evidence Base Lixisenatide Lyxumia Summary The clinical efficacy and safety of lixisenatide were evaluated in nine randomised double-blind, placebo-controlled clinical studies including 4,509 patients type 2 diabetes 24-32. A recent study (published June 2016) comparing once daily liraglutide vs. lixisenatide as add-on therapy to metformin in 404 patients was also included 19. In addition, a 12 week double-blind randomised placebo-controlled study (n=361) was conducted in patients not on glucose lowering therapy. The study found lixisenatide (either 2 step [10mcg for 1 week, 15mcg for week and then 20mcg] or 1 step [10mcg for 2 weeks then 20mcg]) was superior to placebo (either 1 or 2 step) in reduction of HbA1c from baseline (-0.19%, - 0.73%, and -0.85% for combined placebo, lixisenatide 2 step, and lixisenatide 1 step respectively [p<0.0001]) 33. metformin Randomised double-blind placebo controlled study (n=680) in patients on background therapy metformin which compared lixisenatide vs. placebo (morning or evening) found lixisenatide morning injection significantly reduced mean HbA1c vs. combined placebo at 24-weeks (-0.9% vs -0.4%, p<0.0001) 24. Randomised double-blind placebo-controlled study (n=482) in patients on background therapy metformin randomised to receive either lixisenatide in a one-step dose increase or a two-step dose increase vs. placebo for 24 weeks. Lixisenatide one- /two-step once daily significantly improved HbA1c vs. placebo at week 24 (-0.9%, -0.8%, and -0.4%, respectively [p<0.0001]) 25. Non-inferiority study (n= 634) in patients uncontrolled diabetes on background therapy metformin found that lixisenatide 20mcg one daily was non-inferior to exenatide 10mcg twice daily in HbA1c change from baseline to week 24 (- 0.79% vs. -0.96%, respectively) 26. A recent study (published June 2016) comparing once daily liraglutide vs. lixisenatide as add-on therapy to metformin in 404 metformin + ± metformin basal insulin + basal insulin + metformin basal insulin + patients have been described above in the liraglutide table 19. Randomised double-blind placebo controlled study (n=859) in patients inadequately controlled on ± metformin (84% patients on +metformin) found lixisenatide provided a significant reduction in HbA1c at week 24 vs. placebo (-0.85% vs -0.10%, p<0.0001) 27. Randomised double-blind placebo-controlled study (n=391) in Asian patients uncontrolled on metformin ± (44.6%) found at week 24 reduction in HbA1c from baseline was significantly greater lixisenatde vs. placebo (-0.83% vs. - 0.47%, p=0.0004) 28. Randomised double-blind placebo-controlled study (n=484) in patients on at a stable dose of 30mg/day±metformin on a stable dose of 1500mg/day (81% of patients included in the study were on both and metformin) found after 24 weeks, lixisenatide once daily significantly improved HbA1c vs. placebo (-0.9% vs. -0.34%, p<0.0001) 29. Randomised double-blind placebo-controlled study (n=311) found that in Asian patients insufficiently controlled on basal insulin ± (70% on both), lixisenatide was superior in reducing HbA1c at week 24 compared to placebo (-0.77% vs. +0.11%, respectively [p<0.0001]) 30. Randomised double-blind placebo-controlled study (n=446) in patients HbA1c 7-10% despite oral therapy in whom insulin glargine was added and systematically titrated during a 12 week run-in. Adding lixisenatide after run-in further reduced HbA1c by 0.71% vs. 0.40% placebo (p<0.0001) at 24 weeks. All patients included in the study were on background therapy metformin (stable dose of at least 1500mg/day for at least last 3 months), 12% of participants were also on thiazolidenediones 31. Randomised double-blind placebo-controlled study (n=495) in patients inadequately controlled on basal insulin ± metformin (79% of patients on metformin) found lixisenatide was superior in reduction of HbA1c from baseline at 24 weeks compared to placebo (-0.6% vs. -0.3%) 32. 8

Drug Preparation License Evidence Base Dulaglutide Trulicity Summary The safety and efficacy of dulaglutide was evaluated in six randomised, controlled, phase III trials involving 5,171 patients type 2 diabetes. All six studies compared dulaglutide to an active comparator, and one of the studies was both active and placebo controlled 34-39. Monotherapy Active controlled study (n=807) was designed to detect non-inferiority of dulaglutide 1.5mg versus metformin on HbA1c change from baseline at 26-weeks. If non-inferiority was met, superiority was assessed. The study found monotherapy dulaglutide 1.5 mg and 0.75 mg was superior to metformin (1500-2000 mg/day) in the reduction of HbA1c at 26 weeks (-0.78%, -0.71%, and -0.56%, respectively [p<0.025]) 34. metformin One 104-week study (n=1098) found in patients taking metformin, treatment dulaglutide 1.5 mg and 0.75 mg resulted in a superior reduction in HbA1c compared to sitagliptin (100mg daily) at 52 weeks (-1.10%, -0.87%, and - 0.39%, [p<0.025]) 35. An 26-week non-inferiority study (n=599) found in patients taking metformin, treatment dulaglutide 1.5 mg was non-inferior to liraglutide 1.8mg in reducing HbA1c from baseline (-1.42% vs. -1.36%, p<0.001 for noninferiority) 36. basal insulin ± metformin metformin + metformin + Non-inferiority study (n=884) in which patients discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily, both in combination prandial insulin lispro three times daily, or out metformin. The same statistical model was used to assess non-inferiority and superiority of dulaglutide doses versus glargine, a gatekeeping strategy to control family-wise type 1 error rate. At 26 weeks, both 1.5 mg and 0.75mg dulaglutide were superior to insulin glargine in lowering of HbA1c (-1.64%, -1.59%, and - 1.41%, respectively [p<0.025 for superiority]) 37. Open-label comparator randomised controlled study (n=807) found at 52 weeks dulaglutide 1.5mg was superior to insulin glargine for reduction of HbA1c from baseline in patients taking both metformin+ (1.08% vs. - 0.63%, p<0.025 for superiority). Dulaglutide 0.75 mg was non-inferior to insulin glargine(-0.76% vs. -0.63%, p< 0.025 for noninferiority). The study was designed 90% power to show non-inferiority of dulaglutide 1.5mg vs. insulin glargine for change from baseline HbA1c at the 52-week primary endpoint, if non-inferiority was achieved, tree-gatekeeping was used to control the type 1 error rate at 0.025 while assessing the superiority of dulaglutide 1.5 mg versus glargine and the non-inferiority or superiority of dulaglutide 0.75 mg versus glargine for the change from baseline in HbA1c at 52 weeks 38. In a placebo and active (exenatide twice daily) controlled study (n=976), in combination metformin and, dulaglutide 1.5 mg and 0.75 mg demonstrated superiority for HbA1c reduction in comparison to placebo at 26-weeks (-1.51%, -1.30% and -0.46%, respectively [p<0.001]). The study was powered to assess the non-inferiority of dulaglutide vs. exenatide, but analysis found that both strengths of dulaglutide (1.5mg and 0.75mg) were superior to exenatide 10 mcg for HbA1c reduction (-1.51%, -1.30%, and -0.99%, respectively [p<0.025]) 39. 9

Drug Preparation License Evidence Base Albiglutide Eperzan Summary The safety and efficacy of albiglutide was evaluated in eight active and placebo-controlled phase III clinical trials including a total of 4,840 patients type 2 diabetes 40. Studies evaluated the use of albiglutide 30 mg and 50 mg once weekly, allowing for optional titration of albiglutide from 30 mg to 50 mg once weekly in 5 of the 8 studies. In addition to the seven studies described below, the efficacy of albiglutide was also evaluated in a 32-week randomised, open-label, liraglutide-controlled non-inferiority study (n=808) in patients inadquately controlled on monotherapy or combination therapy metformin, a thiazolidenedione, or ). Treatment albiglutide did not meet the pre-specified noninferiority margin (0.3%) against liraglutide for change in HbA1c from baseline at 32 weeks (-0.8% vs. -1.0%, p=0.0846) 40. Monotherapy Study (n=296) in patients inadequately controlled on diet or exercise found treatment albiglutide 30mg and 50mg weekly resulted in statistically significant reductions in HbA1c from baseline at 52 weeks vs. placebo ( -0.70%, -0.9%, and +0.2% respectively [p<0.05 for treatment difference]) 40. metformin Study (n = 999) of patients on background therapy of metformin 1,500 mg daily. Albiglutide 30 mg weekly ( optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared to sitagliptin 100 mg daily, glimepiride 2 mg daily ( optional titration to 4 mg daily), or placebo. At 104 weeks, albiglutide was statistically superior in reduction in HbA1c from baseline compared to placebo, sitagliptin, or glimepiride (-0.6%, +0.3%, -0.3% and -0.4%, respectively [p<0.05 for treatment difference]) 40. metformin ± Study (n=657) in patients on background therapy of metformin 1,500 mg daily+glimepiride 4 mg daily, albiglutide 30 mg SC weekly ( optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared to placebo or 30 mg daily ( optional titration to 45 mg/day) found at 52 weeks treatment albiglutide resulted in statistically significant reductions from baseline in HbA1c compared to placebo (-0.6% versus + 0.33%, p<0.05 for treatment difference). Treatment albiglutide did not meet the pre-specified noninferiority margin (0.3%) against for HbA1c 40. Non-inferiority study of albiglutide vs. insulin-glargine (n=735) in patients on background of metformin 1,500 mg daily ± found at 52 weeks, change in HbA1c was -0.7% and -0.8%, respectively. Albiglutide was noninferior to insulin glargine as the between-treatment difference in HbA1c from baseline at 52 weeks met the prespecified noninferiority margin (0.3%) 40. Study (n=299) in which albiglutide 30 mg weekly was compared to placebo in patients inadequately controlled on 30 mg daily± metformin 1,500 mg daily. At 52 weeks, treatment albiglutide resulted in statistically significant reductions from baseline in HbA1c vs. placebo (-0.8% vs. -0.1% for placebo, p<0.05) 40. insulin glargine Non-inferiority study (n=563) of patients on background therapy insulin glargine compared albiglutide 30 mg once weekly ( up titration to 50 mg if inadequately controlled after Week 8) to prandial insulin lispro. Albiglutide was found to be non-inferior to insulin lispro the between-treatment difference in HbA1c of 0.2% for albiglutide and insulin lispro (-0.8% and -0.6%, respectively) at 26 weeks meeting the pre-specified noninferiority margin (0.4%) 40. 10

* Published Phase 3 studies unless cited as unpublished data cited in summary of product characteristics. References 1. DeFronzo R et al. Effects of Exenatide (Exendin-4) On Glycemic Control and Weight Over 30 Weeks in Metformin-Treated Patients Type 2 Diabetes. Diabetes Care 2005;28:1092-1100 2. Buse JB et al. Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 weeks in Sulfonylurea-Treated patients With Type 2 Diabetes. Diabetes Care 2004;27:2628-2635 3. Kendall D et al. Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Patients With Type 2 Diabetes Treated With Metformin and a Sulfonylurea. Diabetes Care 2005;28:1083 1091 4. Summary of Product Characteristics: Byetta 5 micrograms solution for injection, prefilled pen. Byetta 10 micrograms solution for injection, prefilled pen. Last revised: 16th December 2015. AstraZeneca UK Limited. Accessed online via: www.medicines.org.uk on 29/07/2016 5. Buse JB et al. Use of Twice-Daily Exenatide in Basal Insulin Treated Patients With Type 2 Diabetes: A Randomized, Controlled Trial. Annals of Internal Medicine 2011;154:103-112. 6. Russell-Jones D et al. Efficacy and Safety of Exenatide Once WeeklyVersus Metformin,Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive PatientsWith Type 2 Diabetes (DURATION-4). Diabetes Care 2012;35:252-258 7. Bergenstal RM et al. Efficacy and safety of exenatide once weekly versus sitagliptin or as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010;376:431-39 8. Diamant M et al. Once weekly exenatide compared insulin glargine titrated to target in patients type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 2010;375:2234-43 9. Drucker D et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008;372:1240-50 10. Blevins T et al. DURATION-5: Exenatide Once Weekly Resulted in Greater Improvements in Glycemic Control Compared Exenatide Twice Daily in Patients Type 2 Diabetes. Journal of Clinical Endocrinology & Metabolism 2011;96(5):1301-1310 11. Buse JB et al. Exenatide once weekly versus liraglutide once daily in patients type 2 diabetes (DURATION- 6): a randomised, open-label study. Lancet 2013;381:117-24 12. Summary of Product characteristics: Victoza 6mg/ml solution for injection in pre-filled pen. Last revised: 05/2016. Novo Nordisk Limited. Accessed online via: www.medicines.org.uk on 28/07/2016 13. Nauck M et al. Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes. Diabetes Care 2009;32:84-90 14. Marre M et al. Liraglutide, a once-daily human GLP-1 analogue, added to a over 26 weeks produces greater improvements in glycaemic and weight control compared adding rosiglitazone or placebo in subjects Type 2 diabetes (LEAD-1 SU). Diabetic Medicine 2009;26:268-278 15. Russell-Jones D et al. Liraglutide vs insulin glargine and placebo in combination metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+su): a randomised controlled trial. Diabetologia 2009;52:2046-2055 16. Buse JB et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multi-national, open-label trial (LEAD-6). Lancet 2009 Jul 4;374(9683):39-47 17. Zinman B et al. Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met TZD). Diabetes Care 2009;32:1224-1230 18. Mathieu C et al. A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects type 2 diabetes (BEGIN: VICTOZA ADD-ON). Diabetes, Obesity and Metabolism 2014;16(7):636-44 19. Nauck M et al. Once-Daily Liraglutide Versus Lixisenatide as Add-on to Metformin in Type 2 Diabetes: A 26-week Randomized Controlled Clinical Trial. Diabetes Care 2016; dc152479. http://dx.doi.org/10.2337/dc15-2479 20. Summary of Product Characteristics: Xultophy 100 units/ml insulin deguladec + 3.6mg/mL liraglutide solution for injeciton in a pre-filled pen. Last revised: 02/2016. Novo Nordisk Limited. Accessed online via: www.medicines.org.uk on 29/07/2016 21. Lingvay I. Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes - The DUAL V Randomized Clinical Trial. JAMA. 2016:315(9):898-907 22. Gough S et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients type 2 diabetes. Lancet 2014;2:885-93 23. Buse JB et al. Contribution of Liraglutide in the Fixed-Ratio Combination of Insulin Degludec and Liraglutide (IDegLira). Diabetes Care 2014;37:1 8 11

24. Ahrén B et al. Efficacy and Safety of Lixisenatide Once-Daily Morning or Evening Injections in Type 2 Diabetes Inadequately Controlled on Metformin (GetGoal-M). Diabetes Care 2013;36:2543-2550 25. Bolli GB et al. Efficacy and safety of lixisenatide oncedaily vs.placebo in people Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabetic Medicine 2014;31:176-184 26. Rosenstock J et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 2013;36(10):2945-51 27. Rosenstock J et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels out significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea or out metformin (GetGoal-S). Journal of Diabetes and its Complications 2014;28(3):386-92 28. Pan CY et al. Lixisenatide in Asian Patients Type 2 Diabetes (T2DM) Uncontrolled on Metformin ± Sulfonylurea (SU): GetGoal-M Asia. Diabetes/Metabolism Research and Reviews 2014;30(8):726-35 29. Pinget M et al. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on (GetGoal-P). Diabetes, Obesity and Metabolism 2013;15:1000-1007 30. Seino Y et al. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients type 2 diabetes insufficiently controlled on basal insulin or out a sulfonylurea (GetGoal-L-Asia). Diabetes Obesity and Metabolism 2012;14(10):910-917 31. Riddle M et al. Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled With Newly Initiated and Continuously Titrated Basal Insulin Glargine. Diabetes Care 2013;36:2497-2503 32. Riddle M et al. Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin. Diabetes Care 2013;36:2489-2496 33. Fonseca V et al. Efficacy and Safety of the Once-Daily GLP-1 Receptor Agonist Lixisenatide in Monotherapy. Diabetes Care 2012;35:1225-1337 34. Umpierrez G et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 2014;37(8): 2168-2176 35. Nauck M et al. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care 2014;37(8):2149-2158 36. Dungan K M et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients type 2 diabetes (AWARD-6): A randomised, open-label, phase 3, non-inferiority trial. Lancet 2014;384:1349-1357 37. Blonde L et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination prandial insulin lispro in patients type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, noninferiority study. Lancet 2015;385:2057-2066 38. Giorgino F et al. Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients type 2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care 2015;38(12): 2241-2249 39. Wysham C et al. Efficacy and Safety of Dulaglutide Added onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1). Diabetes Care 2014;37(8):2159-2167 40. Summary of Product Characteristics: Eperzan 30mg powder and solvent for solution for injection. Last revised: 31st March 2016. GlaxoSmithKline UK. Accessed online via: www.medicines.org.uk on 29/07/2016 Bibliography Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com Electronic Medicines Compendium accessed online via: www.medicines.org.uk National Institute for Health and Care Excellence. Diabetes Type 2 diabetes in adults: management NICE guidelines [NG28] Published date: December 2015 UpToDate. Wolters Kluwer. http://www.uptodate.com/home/ European Medicines Agency http://www.ema.europa.eu/ema/ Author Suhayla Dhanji Contact details Suhayla Dhanji/David Erskine, London Medicines Information Service: medicinesinformation@gstt.nhs.uk 12