Selecting GLP-1 RA Treatment - PDF Free Download

Selecting GLP-1 RA Treatment Dr Felicity Kaplan March 2017

Objectives Review the progressive nature of type 2 diabetes Understand the need for timely treatment intensification Examine the place of GLP-1 receptor agonists (GLP-1 RA) in guidelines Compare the attributes of different GLP-1 RA products available in the UK

Progressively declining beta cell function in T2D waiting for failure 100 Lifestyle Monotherapy Dual therapy Insulin ±oral drugs for lowering blood glucose 10 9 8 7 6 0 0 HbA 1c ß-cell function Time (years) 5 0 >15 T2D=Type 2 diabetes mellitus. Data from Heine RJ et al. BMJ. 2006; 333: 1200 1204.

New drug treatments in the last 10 years Biosimilar glargine 11 Insulin + GLP-1 RA fixed combination 12 Insulin lispro 200 units/ml 1 (renewal; first authorisation 1996) GLP-1 RA (twice daily) Exenatide BID 2 DPP-4-i + metformin fixed combination 3 DPP-4-i Sitagliptin 4 Insulin glargine 300 units/ml 5 GLP-1 RA (once daily) Liraglutide 6 GLP-1 RA (once weekly) Exenatide QW 7 SGLT2 Inhibitors Dapagliflozin 8 SGLT2-i + metformin fixed combination 13 Insulin degludec 200 units/ml 9 GLP-1 RA (once daily) Lixisenatide 10 GLP-1 RA (once weekly) Albiglutide 14 GLP-1 RA (once weekly) Dulaglutide 15 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Date of Marketing Authorisation in the UK 1. Humalog 200 units/ml Summary of Product Characteristics. 2. Byetta Summary of Product Characteristics. 3. Eucreas Summary of Product Characteristics. 4. Januvia Summary of Product Characteristics. 5. Toujeo Summary of Product Characteristics. 6. Victoza Summary of Product Characteristics. 7. Bydureon Summary of Product Characteristics. 8. Forxiga Summary of Product Characteristics. 9. Tresiba Summary of Product Characteristics. 10. Lyxumia Summary of Product Characteristics. 11. Abasaglar Summary of Product Characteristics. 12. Xultophy Summary of Product Characteristics. 13. Xigduo Summary of Product Characteristics. 14. Eperzan Summary of Product Characteristics. 15. Trulicity Summary of Product Characteristics.

Despite the addition of new treatment options, many patients with type 2 diabetes are not meeting their treatment goals 35.2% A recent national diabetes audit showed that 35.2% of patients with type 2 diabetes have HbA 1c >58mmol/mol (7.5%) 1 Many patients are not meeting their outcome goals on oral therapy 2, increasing the risk of complications 3 1. Health & Social Care Information Centre (HSCIC). National Diabetes Audit 2012 2013: Report 1, Care Processes and Treatment Targets. October 2014. Available at: http://www.hscic.gov.uk/catalogue/pub14970/nati-diab-audi-12-13-care-proc-rep.pdf [Last Accessed: December 2015]. 2. Casagrande S et al. Diabetes Care 2013; 36(8): 2271 2279. 3. Inzucchi SE et al. Diabetes Care. 2015; 38: 140 149.

The treatment intensification challenge How long do people with type 2 diabetes wait for therapy intensification despite an HbA 1c 58 mmol/mol (7.5%)? HbA 1c 58 mmol/mol (7.5%) Time to next intensification (median) 1 On 1x OAD On 2x OADs 1.9 years 7.2 years 50% of patients may be uncontrolled on oral therapy for an average of 5 years before moving onto an injectable 2 1. Khunti K et al. Diabetes Care 2013; 36: 3411 3417. 2. Rubino A et al. Diabetic Medicine 2007; 24: 1412 1418.

The potential reward for improved control Every 1% reduction in HbA 1c REDUCED RISK Fatal or non-fatal MI 14% 1% Deaths from diabetes 21% Microvascular complications 37% Amputation or death from peripheral vascular disorders 43% Data from Stratton IM et al. BMJ 2000; 321: 405 412.

% Patients at this level before Delayed initiation of GLP-1 RAs in the UK IMS localised data The NICE guideline 28 recommends initiation of GLP-1 RA therapy in combination with metformin and sulphonylurea when triple therapy with metformin and two other oral medications is not effective, or tolerated or contraindicated, fails to maintain an HbA 1c 58 mmol/mol ( 7.5%, or other higher level agreed with the patient) and the patient meets one of the following criteria a BMI of 35 kg/m 2 or higher (adjust accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or a BMI lower than 35 kg/m 2 and for whom insulin therapy would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities In the UK 72% of patients are initiated on a GLP-1 receptor agonist at an HbA 1c of 8.5% 2 35% 33% starting GLP-1 RA Therapy* 2 30% 25% 20% 15% 10% 5% 0% 3% 3% <7.0 7.0 <7.5 9% 7.5 <8.0 13% 8.0 <8.5 12% 8.5 <9.0 16% 9.0 <9.5 11% 9.5 <10.0 10.0 *n=14,623 HbA 1c (%) 1. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guideline 28. London: NICE; December 2015 (http://www.nice.org.uk/guidance/ng28) [Last Accessed: January 2016]. 2. Data on File. IMS data May 2015, HbA 1C level before starting GLP-1 Receptor Agonist Therapy. Eli Lilly and Company; 2015.

Why is there a delay in initiating injectable therapy? Attitudes toward the initiation of insulin may delay escalation to other injectable therapies 1 Clinicians People with type 2 diabetes Challenges with insulin selection and titration Burdensome patient counselling requirements Avoidance of patient burden Concern over hypoglycaemic risk (insulin-specific) Lifestyle and employment restrictions Fear of hypoglycaemia (insulin-specific) Anxiety about injecting Concern about weight gain 1. Korytkowski M. Int J Obes Relat Metab Disord. 2002; 26(Suppl3): S18 24.

Treatment intensification with GLP-1 RAs may be an attractive option for people with type 2 diabetes Despite the potential for improved glycaemic control, many people with type 2 diabetes are reluctant to start injectable therapy 1 GLP-1 RAs offer the following benefits: HbA 1c reductions 2 Low risk of hypoglycaemia 2 Potential for weight loss 2 Development of GLP-1 RAs over time has allowed the option of less frequent injections for patients 2006 3 2009 4 2011 5 Twice daily Once daily Once weekly 1. Garcia-Perez L et al. Diabetes Ther 2013; 4: 175 194. 2. Freeman JS. J Am Osteopath Assoc. 2011; 111(2 suppl 1): es15-es20. 3. Byetta Summary of Product Characteristics. 4. Victoza Summary of Product Characteristics. 5. Bydureon Summary of Product Characteristics.

ADA/EASD Joint Position Statement: The guidelines highlight where GLP-1 RAs can be used in combination: Strategy progression after 3 months of unsuccessful glycaemic control (HbA 1c target) Initial drug monotherapy 2-drug combinations 3-drug combinations Combination injectable therapy Metformin (or SU if metformin not tolerated) Metformin + SU TZD Metformin + SU + TZD or DPP-4-i or SGLT2-i or GLP-1 RA or insulin TZD + SU or DPP-4-i or SGLT2-i or GLP-1 RA or insulin Metformin + Basal insulin + mealtime insulin or GLP-1 RA DPP-4-i DPP-4-i or SU or TZD or SGLT2-i or insulin SGLT2-i SGLT2-i + SU or TZD or insulin GLP-1 RA GLP-1 RA + SU or TZD or insulin Insulin (usually basal) Insulin + TZD or DPP-4-i + SGLT2-i or GLP-1 RA ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; DPP-4-I=Dipeptidyl peptidae-4 inhibitor; SGLT2-I=Sodium-glucose transporter 2 inhibitor; GLP-1 RA=Glucagon-like peptide-1 receptor agonist; SU=Sulphonylurea; TZD=Thiazolidinedione. Inzucchi SE et al. Diabetes Care 2015; 38: 140 149.

NICE NG28: algorithm for blood glucose lowering therapy in adults with type 2 diabetes 1. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guideline 28. London: NICE; December 2015 (http://www.nice.org.uk/guidance/ng28) [Last Accessed: January 2016]. Reproduced with permission.

Treatment attributes of various drug choices for type 2 diabetes Metformin + SU TZD DPP-4-i SGLT2-i GLP-1 RA Efficacy* High High intermediate intermediate High Hypo risk Moderate Low Low Low Low Weight** Gain Gain Neutral Loss Loss Side effects Hypoglycaemia Oedema, HF Rare GU, dehydration GI Cost Low Low High High High *Reduction in HbA 1c **Not licensed for weight loss Additional selection criteria Blood pressure PPG Potential dual therapy options for people with type 2 diabetes are displayed. It is not meant to denote any specific preference. ADA, Standards of Medical Care in Diabetes, section 7. Approaches to Glycemic Treatment Diabetes Care 2015; 38(Suppl. 1): S41 S48.

Different GLP-1 RAs as add-on to metformin data derived from clinical trials Dose Dosing frequency Change in HbA 1c Change in weight (kg) Exenatide 1 10 μg Twice daily 0.8% 2.8 Liraglutide 2 1.2 mg 1.3% 2.6 Once daily 1.8 mg 1.3% 2.8 Lixisenatide 3 20 μg Once daily 0.8% 3.0 Exenatide 4 2 mg Once weekly 1.5% 2.3 Trulicity 5 1.5 mg Once weekly 1.4% 2.9 Albiglutide 6 30 mg Once weekly 0.9% 1.2 1. DeFronzo RA et al. Diabetes Care 2005; 28: 1092 1100. 2. Nauck M et al. Diabetes Care 2009; 32: 84 90. 3. Rosenstock J et al. Diabetes Care 2013; 36: 2945 2951. 4. Bergenstal RM et al. Lancet 2010; 376: 431 439. 5. Dungan KM et al. Lancet 2014; 384: 1349 1357. 6. Ahrén B et al. Diabetes Care 2014; 37: 2141 2148.

GLP-1 RAs as part of triple therapy data derived from clinical trials Dose Background therapy Change in HbA 1c Change in weight (kg) Exenatide BID 1 10 μg Metformin + SU -0.8% -1.6 kg Exenatide QW 2,3 2 mg Oral antihyperglycaemic drugs -1.3% -2.7 kg Included patients treated with metformin, SU, TZD alone or in combination -2.0% -4.1 kg Liraglutide 4 1.8 mg Metformin + TZD (rosiglitazone) -1.5% -2.0 kg Metformin + glimepiride -1.3% -1.8% 1.2 mg Metformin + TZD (rosiglitazone) -1.5% -1.0 kg Lixisenatide 5 20 μg Metformin + SU -0.9% -1.8 kg Trulicity 6 1.5 mg Metformin + SU -1.1% -1.9 kg Metformin + TZD (pioglitazone) -1.5% -1.3 kg Albiglutide 7 30 mg Metformin + glimepiride -0.6% -0.4 kg Metformin + SU -0.7% -1.1 kg 1. Kendall D et al. Diabetes Care 2005; 28: 1083 1091. 2. Buse J et al. Diabetes Care 2010; 33: 1255 1261. 3. Buse J et al. Lancet 2013: 381: 117 124. 4. Victoza Summary of Product Characteristics. Novo Nordisk Ltd. 5. Rosenstock J et al. Journal of Diabetes and its complications 2014; 28: 386 392. 6. Trulicity Summary of Product Characteristics. 7. Eperzan Summary of Product Characteristics.

Different GLP-1 RAs: licensed indications and special populations Guidance on use Indication in type 2 diabetes In renal impairment In the elderly + insulin Exenatide BID 1 In combination with: metformin, SU, TZD or metformin + SU, metformin + TZD in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies Mild Moderate (approach dose escalation conservatively) Use with caution also indicated as adjunctive therapy to basal insulin +/- metformin and/or pioglitazone in adults who have not achieved adequate glycaemic control with these agents Exenatide QW 2 In combination with: metformin, SU, TZD or metformin + SU, metformin + TZD in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies Mild only No dose adjustment required; consideration to renal function with older age Not reported Liraglutide 3 To achieve glycaemic control as: Monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance or contraindications Combination therapy In combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4 and 5.1 for available data on the different combinations) Mildmoderate No dose adjustment required Can be used in combination with basal insulin Lixisenatide 4 To achieve glycaemic control in combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control Mildmoderate No dose adjustment required Can be used in combination with basal insulin 1. Byetta Summary of Product Characteristics. 2. Bydureon Summary of Product Characteristics. 3. Victoza Summary of Product Characteristics. 4. Lyxumia Summary of Product Characteristics.

Different GLP-1 RAs: licensed indications and special populations Guidance on use Indication in type 2 diabetes In renal impairment In the elderly + insulin To improve glycaemic control as: Trulicity 1 Monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications Add-on therapy in combination with other glucoselowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control Mildmoderate No dose adjustment required; 75 years consider 0.75 mg dose Can be used in combination with insulin To improve glycaemic control as: Albiglutide 2 Monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to contraindications or intolerance Add-on combination therapy in combination with other glucose-lowering medicinal products including basal insulin, when these, together with diet and exercise, do not provide adequate glycaemic control Mildmoderate No dose adjustment required Can be used in combination with insulin 1. Trulicity Summary of Product Characteristics. 2. Eperzan Summary of Product Characteristics.

Different GLP-1 RAs, different devices and practical considerations Dose Need to reconstitute Needle included Hidden needle Needle gauge Exenatide BID a,1,2 10μg NO 29, 30 or 31 Liraglutide QoD b,3 1.2mg NO 32 Liraglutide QoD b,3 1.8mg Lixisenatide QoD b,4 20μg NO 29 to 32 Exenatide QW b,5,6 2 mg YES 23 Trulicity QW b,7 1.5 mg NO 29 Albiglutide QW b,8,9 30mg YES 29 a: 60 minutes before 2 main meals (6 hours apart) b: any time of day, independent of meals 1. Byetta Summary of Product Characteristics. 2. About the Byetta pen. Available at: https://www.byetta.com/getting-started-on-byetta/about-the-byetta-pen. [Last accessed: April 2016]. 3. Victoza Summary of Product Characteristics. 4. Lyxumia Summary of Product Characteristics. 5. Bydureon Summary of Product Characteristics. 6. Bydureon Frequently Asked Questions. Available at: https://www.bydureon.com/using-bydureon/bydureon-faqs.html. [Last accessed: April 2016]. 7. Trulicity Summary of Product Characteristics. 8. Eperzan Summary of Product Characteristics. 9. European Medicines Agency. Eperzan Assessment Report. Available at: http://www.ema.europa.eu/docs/en_gb/document_library/epar_-_public_assessment_report/human/002735/wc500165119.pdf. [Last accessed: April 2016].

Dulaglutide offers significant HbA 1c reduction in a ready-to-use pen with once-weekly dosing 1 Trulicity is indicated in adults with type 2 diabetes mellitus to improve glycaemic control as: Monotherapy 0.75 mg once weekly When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications. Add-on therapy 1.5 mg once weekly In combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. For potentially vulnerable populations, such as patients 75 years, 0.75 mg once weekly can be considered as a starting dose Trulicity 1.5 mg demonstrated statistically superior HbA 1c reduction in phase III clinical trials vs metformin, exenatide BID, insulin glargine, and sitagliptin. Trulicity 1.5mg demonstrated statistically noninferior HbA 1c reduction vs liraglutide 1.8 mg in 1 phase III trial. 1. Trulicity Summary of Product Characteristics

HbA 1c change from baseline ±SE (%, LS mean) HbA 1c change from baseline ±SE (%, LS mean) In a post-hoc analysis of patients from Award 1, Trulicity achieved HbA 1c reductions >2% in the subgroup of patients with a baseline HbA 1c 8.5% 1 In the UK 72% of patients are initiated on a GLP-1 receptor agonist at an HbA 1c of 8.5%* 2 0-0.4-0.8-1.2-1.6-2.0-2.4-1.16% <8.5% (69.4 mmol/mol) -0.64% -0.17% HbA 1c reduction 0-02 -04-06 -08-10 -12-14 -16-18 -20-22 -24-26 HbA 1c change from baseline ±SE (mmol/mol, LS mean) 0-0.4-0.8-1.2-1.6-2.0-2.4-2.37% 8.5% (69.4 mmol/mol) -1.86% -0.76% 0-02 -04-06 -08-10 -12-14 -16-18 -20-22 -24-26 HbA 1c change from baseline ±SE (mmol/mol, LS mean) P 0.001 vs placebo P<0.001 vs exenatide Comparisons are within each baseline HbA 1c cohort Trulicity 1.5 mg (n=191; baseline 7.4% [57.4 mmol/mol]) Exenatide BID (n=192; baseline 7.3% [56.3 mmol/mol]) Placebo (n=92; baseline 7.3% [56.3 mmol/mol]) Trulicity 1.5 mg (n=88; baseline 9.7% [82.5 mmol/mol]) Exenatide BID (n=84; baseline 9.8% [83.6 mmol/mol]) Placebo (n=49; baseline 9.6% [81.4 mmol/mol]) *Patients had their HbA 1c recorded in the 6 months prior to initiation of GLP-1 therapy 1. Bain S et al. Poster presented at the PCDS 2015; 5 6 November, Birmingham 2. Data on File. IMS data May 2015, HbA 1C level before starting GLP-1 Receptor Agonist Therapy. Eli Lilly and Company; 2015.

Rate of symptomatic hypoglycaemia (episodes/patient/year) Hypoglycaemia with Trulicity 1.5 mg Rates of documented symptomatic hypoglycaemia* 3.2 3 AWARD-2 With background sulphonylurea Add-on to metformin and a sulphonylurea 3.02 AWARD-6 Without background sulphonylurea Add-on to metformin AWARD-1 Add-on to metformin and pioglitazone 2.8 2.6 2.4 2.2 2 1.8 1.67 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 Trulicity 1.5 mg (n=273) 0.12 0.29 Trulicity 1.5 mg (n=299) 0.19 0.75 Trulicity 1.5 mg (n=279) Insulin glargine (n=262) Liraglutide (n=300) Exenatide BID (n=276) Please be aware: Patients receiving Trulicity in combination with a sulphonylurea or prandial insulin may have an increased risk of hypoglycaemia. The risk may be lowered by reducing the dose of sulphonylurea or insulin. 1 *Documented symptomatic hypoglycaemia and blood glucose 3.9 mmol/l. 1 Trulicity Summary of Product Characteristics.

Patients (%) Incidence of nausea was comparable with Trulicity 1.5 mg and liraglutide 1.8 mg in a head-to-head trial 1 50 40 30 Trulicity 1.5 mg (n=299) Liraglutide 0.6 mg 1.2 mg 1.8 mg titrated over the first 3 weeks of treatment (n=300) 20 10 0 0 1 2 4 8 12 20 26 Time (weeks) 1. Dungan KM et al. Lancet. 2014; 384(9951): 1349 1357.

Pancreatic safety Acute pancreatitis Use of GLP-1 associated with a risk of pancreatitis Pancreatitis has been reported with Trulicity. The incidence of acute pancreatitis in phase 2 and 3 clinical studies was 0.07% for Trulicity compared to 0.14% for placebo and 0.19% for comparators with or without additional background antidiabetic therapy The recommended dose for Trulicity is 1.5 mg when prescribed as add-on therapy. In AWARD-1, AWARD-2, AWARD-4 and AWARD-5, additional groups received Trulicity 0.75 mg, which is the recommended dose for monotherapy or can be considered as a starting dose in potentially vulnerable populations such as patients 75 years of age. Trulicity Summary of Product Characteristics.

List price and cost per day of GLP-1 receptor agonists *Needles included in list price **Cost refers to the maintenance dose of 20 micrograms once daily 5 All figures have been rounded to 2 decimal places 1. Liraglutide MIMS. Available at: http://www.mims.co.uk/drugs/diabetes/oral-and-parenteral-hypoglycaemics/victoza. [Last Accessed: February 2016]. 2. Exenatide QW MIMS. Available at: http://www.mims.co.uk/drugs/diabetes/oral-and-parenteral-hypoglycaemics/bydureon. [Last Accessed: February 2016]. 3. Albiglutide MIMS. Available at: http://www.mims.co.uk/drugs/diabetes/oraland-parenteral-hypoglycaemics/eperzan. [Last Accessed: February 2016]. 4. Exenatide BD MIMS. Available at: http://www.mims.co.uk/drugs/diabetes/oral-and-parenteral-hypoglycaemics/byetta. [Last Accessed: February 2016]. 5. Lixisenatide MIMS. Available at: http://www.mims.co.uk/drugs/diabetes/oral-and-parenteral-hypoglycaemics/lyxumia. [Last Accessed: February 2016].

Summary We need to take a proactive approach in the management of glycaemic control in type 2 diabetes Despite the introduction of new therapies, clinical inertia results in many patients not meeting their glycaemic goals GLP-1 RAs offer the potential for glycaemic control with a low risk of hypoglycaemia and the potential for weight loss NICE recommends after 3 oral agents 1 Choice of GLP-1 treatment should be based on: 1 the person's individual clinical circumstances, preferences and needs in addition to effectiveness safety, tolerability available licensed indications or combinations, and cost if 2 drugs in the same class are appropriate, choose the option with the lowest acquisition cost 1. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guideline 28. London: NICE; December 2015 (http://www.nice.org.uk/guidance/ng28) [Last Accessed: January 2016].

Dulaglutide has received positive opinion from the CHMP; however, there is no guarantee it will receive regulatory approval and become commercially available in your affiliate.

UKDUA00278(2) December 2016

NICE Guideline The latest update to the NICE type 2 diabetes guideline (NG28) now recommends that treatment choice should take individual needs into account 1 The choice of drug treatment should consider: the person's individual clinical circumstances, preferences and needs in addition to effectiveness safety, tolerability available licensed indications or combinations, and cost if 2 drugs in the same class are appropriate, choose the option with the lowest acquisition cost NICE guideline 28 also updates and replaces the single technology appraisals for liraglutide (TA203) and exenatide (TA248) 1 Therefore there is no longer mandatory funding for liraglutide and exenatide once-weekly 1. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guideline 28. London: NICE; December 2015 (http://www.nice.org.uk/guidance/ng28) [Last Accessed: January 2016].

Patient preference and needs The choice of drug treatment should consider the person s individual clinical circumstances, individual preferences and needs, safety, cost (if 2 drugs in the same class are appropriate, choose the option with the lowest acquisition cost), licensed indications or combinations available in addition to effectiveness of the drug treatment(s) in terms of metabolic response (NICE NG28) 1 1. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guideline 28. London: NICE; December 2015 (http://www.nice.org.uk/guidance/ng28) [Last Accessed: January 2016].

Both the Trulicity molecule and the pen were designed with these patients in mind The Patient Clinical profile Has type 2 diabetes* and: currently on oral medications only HbA 1c between 7.5% and 9.0% weight is a clinical concern Lifestyle considerations Wants to succeed, but: struggles to fit changes into a busy life disappointed about not reaching goals Needs to start an injectable therapy for the first time, but like many patients is reluctant to do so Trulicity Efficacy evaluated in phase III clinical trials in this patient population 1 7 Body weight change evaluated as secondary endpoint 1 7 An extended half-life for once-weekly dosing 1 Solubility to avoid the need for reconstitution 8,9 Ready-to-use pen 10 No need to see or touch needle 10 Once-weekly dosing 1 *hypothetical patient 1. Trulicity Summary of Product Characteristics. 2. Wysham C et al. Diabetes Care. 2014; 37(8): 2159 2167. 3. Giorgino F et al. Diabetes Care. 2015; 38: 2241 2249. 4. Umpierrez G et al. Diabetes Care. 2014; 37: 2168 2176. 5. Blonde L et al. Lancet. 2015; 385: 2057 2066. 6. Nauck M et al. Diabetes Care. 2014; 37(8): 2149 2158. 7. Dungan KM et al. Lancet. 2014; 384(9951): 1349 1357. 8. Barrington P et al. Diabetes Obesity and Metabolism 2011; 13: 426 433. 9. Data on File. Wolfgang Glaesner interview. Eli Lilly and Company; 2014. 10. Trulicity Instructions for use.

Patient-centred attributes: Results of the dulaglutide molecular design 1 Once-weekly subcutaneous administration Soluble, ready-to-use formulation Reduced renal clearance Low potential for immunogenicity Linker GLP-1 analogue Modified IgG4-Fc domain 1. Trulicity Summary of Product Characteristics.

Ready-to-use pen designed with the patient in mind The Trulicity pen is ready-to-use 1 No reconstitution or priming required Pre-attached, hidden 29-gauge needle Each pen contains a fixed dose of Trulicity Automatic dose delivery at the push of a button 1 Administration that 99% of patients found easy 2 1. Trulicity Instructions for use. 2. Matfin G et al. J Diabetes Sci Technol. 2015; 9(5): 1071 1079.

GLP-1 effects in humans: Understanding the glucoregulatory role of incretins 1 5 Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucose-dependent insulin secretion Liver: Glucagon reduces hepatic glucose output GLP-1 secreted upon the ingestion of food GLP-1 secreted upon the ingestion of food Stomach: Slows gastric emptying 1. Nauck MA et al. Diabetologia 1986; 29: 46 52. 2. Drucker DJ. Diabetes 1998; 47: 159 169. 3. Flint A et al. J Clin Invest 1998; 101: 515 520. 4. Larsson H et al. Acta Physiol Scand 1997; 160: 413 422. 5. Nauck MA et al. Diabetologia 1996; 39: 1546 1553.

Different GLP-1 RAs: safety Very common ( 1 in 10) AEs Exenatide BID 1 Hypoglycaemia (with metformin + SU/ with SU) Nausea, vomiting, diarrhoea Exenatide QW 2 Hypoglycaemia (with SU) Nausea, diarrhoea Liraglutide 3 Nausea, diarrhoea Hypoglycaemia (with SU and/or basal insulin) Lixisenatide 4 Headache Nausea, vomiting, diarrhoea Trulicity 5 Hypoglycaemia (with insulin, glimepiride, metformin or metformin + glimepiride) Nausea, vomiting, diarrhoea, abdominal pain Hypoglycaemia (when used in combination with insulin or sulphonylurea) Albiglutide 6 Diarrhoea, nausea Injection site reactions 1. Byetta Summary of Product Characteristics. 2. Bydureon Summary of Product Characteristics. 3. Victoza Summary of Product Characteristics. 4. Lyxumia Summary of Product Characteristics. 5. Trulicity Summary of Product Characteristics. 6. Eperzan Summary of Product Characteristics.

HbA 1c change from baseline ±SE (%, LS mean) Significant HbA 1c reduction across 6 clinical trials Monotherapy Dual therapy Triple therapy Indicates likely first injectable options Insulin 0-0.2-0.4-0.6-0.8-1.0-1.2-1.4-1.6-1.8 AWARD-3 (26 weeks) -0.56% -0.71%* *P<.025, superiority vs active comparator P<.001, noninferiority vs active comparator AWARD-5 (52 weeks) -1.10%* -0.39% -1.42% AWARD-6 AWARD-1 AWARD-2 (26 weeks) (26 weeks) (52 weeks) -1.36% -1.51%* -0.99% 0.46% -1.08%* -0.63% AWARD-4 (26 weeks) -1.64%* -1.41% 0-2 -4-6 -8-10 -12-14 -16-18 -2.0 HbA 1c change from baseline ±SE (mmol/mol, LS mean) Trulicity 0.75 mg (n=270; baseline 7.58% [59.3 mmol/mol]) Trulicity 1.5 mg (n=304; baseline 8.12% [65.3 mmol/mol]) Trulicity 1.5 mg (n=299; baseline 8.06% [64.6 mmol/mol]) Trulicity 1.5 mg (n=279; baseline 8.10% [65.0 mmol/mol]) Trulicity 1.5 mg (n=273; baseline 8.18% [65.9 mmol/mol]) Trulicity 1.5 mg (n=295; baseline 8.46% [69.0 mmol/mol]) Metformin (n=268; baseline 7.60% [59.6 mmol/mol]) Sitagliptin (n=315; baseline 8.09% [64.9 mmol/mol]) Liraglutide 1.8 mg (n=300; baseline 8.05% [64.5 mmol/mol]) Exenatide BID (n=276; baseline 8.07% [64.7 mmol/mol]) Placebo (n=141; baseline 8.06% [64.6 mmol/mol]) Insulin glargine (n=262; baseline 8.10% [65.0 mmol/mol]) Insulin glargine (n=296; baseline 8.53% [69.7 mmol/mol]) The recommended dose for Trulicity is 1.5 mg when prescribed as add-on therapy. In AWARD-1, AWARD-2, AWARD-4 and AWARD-5, additional groups received Trulicity 0.75 mg, which is the recommended dose for monotherapy or can be considered as a starting dose in potentially vulnerable populations such as patients 75 years of age. Trulicity Summary of Product Characteristics.

Change in body weight (kg) Weight change with Trulicity across phase III clinical trials Weight change at prespecified primary time-point Indicates likely first injectable options Monotherapy Dual therapy Triple therapy Insulin 3.0 2.0 1.0 AWARD-3 (26 weeks) AWARD-5 (52 weeks) AWARD-6 AWARD-1 AWARD-2 (26 weeks) (26 weeks) (52 weeks) +1.24 +1.44 AWARD-4 (26 weeks) +2.33 0-1.0-2.0-3.0-4.0-1.36* -2.22-3.03-1.53-2.90 * -3.61-1.30-1.07-1.87-0.87 *P<.05 vs active comparator P<.001 vs active comparator Trulicity 0.75 mg (n=270) Metformin (n=268) Trulicity 1.5 mg (n=304) Sitagliptin (n=315) Trulicity 1.5 mg (n=299) Liraglutide 1.8 mg (n=300) Trulicity 1.5 mg (n=279) Exenatide BID (n=276) Placebo (n=141) Trulicity 1.5 mg (n=273) Insulin glargine (n=262) Trulicity 1.5 mg (n=295) Insulin glargine (n=296) Trulicity is not indicated for weight loss; weight change was a secondary endpoint in clinical trials. The recommended dose for Trulicity is 1.5 mg when prescribed as add-on therapy. In AWARD-1, AWARD-2, AWARD-4 and AWARD-5, additional groups received Trulicity 0.75 mg, which is the recommended dose for monotherapy or can be considered as a starting dose in potentially vulnerable populations such as patients 75 years of age. Trulicity Summary of Product Characteristics.

HbA 1c Change from Baseline ±SE (%, LS Mean) HbA 1c reduction with Trulicity 1.5 mg once-weekly was noninferior to liraglutide 1.8 mg once daily in a head-to-head trial 1,2 0 0-0.2-2 -0.4-0.6-0.8-1.0-1.2-1.4-1.6-1.42% -1.36% -4-6 -8-10 -12-14 -16-18 HbA 1c Change from Baseline ±SE (mmol/mol, LS Mean) Trulicity 1.5 mg (n=299; baseline HbA 1c : 8.1% [65.0 mmol/mol]) Liraglutide 1.8 mg (n=300; baseline HbA 1c : 8.1% [65.0 mmol/mol]) -1.8-20 P<.0001 Non-inferiority vs liraglutide Data presented are mean values at 26 weeks. LS = least squares; SE = standard error. 1. Trulicity Summary of Product Characteristics. 2. Dungan KM et al. Lancet. 2014; 384(9951): 1349 1357.