Simplifying Anti-Diabetic Treatments Through Patient-Centric Approach

A patient-centric approach can we simplify the use of anti-diabetic treatments? John Buse School of Medicine, University of North Carolina, USA

IDegLira is not marketed in Spain Agenda Common barriers to insulin therapy: Hypoglycaemia Weight gain Regimen complexity GI adverse events in patients treated with IDegLira Patient-reported outcomes in IDegLira clinical trials Real-world studies of IDegLira GI, gastrointestinal

IDegLira is not marketed in Spain IDegLira demonstrated significant improvements in HbA1c across the DUAL programme End-of-treatment HbA1c (%) DUAL VI DUAL I ext. DUAL IV DUAL II DUAL VIII DUAL IX DUAL III DUAL V DUAL VII 1WT 2WT 8.7 8.3 8.5 8.2 8.2 8.2 8.1 8.4 7.9 7.8 -1.9* -1.5* -1.8* -1.8* -1.8* -1.9* -2.0* -2.0* -1.5* -1.3* 6.9 6.7 6.6 6.4 6.4 6.4 6.1 6.4 6.3 6.0 Add to OAD(s) GLP-1 switch Basal insulin switch Across all nine studies, IDegLira decreased mean HbA1c to below 7.0% (6.0 6.9%) *Mean change in HbA1c from baseline to end of trial; HbA1c reduction for patients that remained on IDegLira at Week 104 (n=333) GLP-1 RA, glucagon-like peptide-1 receptor agonist; IAsp; insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; OAD, oral anti-diabetic drug Gough et al. Diabetes Obes Metab 2015;17:965 73; Buse et al. Diabetes Care 2014;37:2926 2933; Linjawi et al. Diabetes Ther 2017;8:101 114; Rodbard et al. Diabet Med 2017;34:189 196; Lingvay et al. JAMA 2016;315:898 907; Harris et al. Diabetes Obes Metab 2017;19:858 865; Billings et al. Diabetes Care 2018;41:1009 1016; Aroda et al. Lancet Diabetes Endocrinol 2019;7:596 605; Philis-Tsimikas et al.Diabetes Obes Metab 2019;21:3199 1408

IDegLira is not marketed in Spain Common barriers to insulin initiation and intensification Weight gain2 Complexity1 Hypoglycaemia1 More than half of T2D patients on basal insulin are not at target HbA1c3 T2D, type 2 diabetes 1. Peyrot et al. Diabet Med 2012;29:682 689; 2. Carver C. Diabetes Educ 2006;32:910 917; 3. Giugliano et al. Diab Care. 2011;34:510 517

IDegLira is not marketed in Spain Common barriers to insulin initiation and intensification Weight gain2 Complexity1 Hypoglycaemia1 More than half of T2D patients on basal insulin are not at target HbA1c3 T2D, type 2 diabetes 1. Peyrot et al. Diabet Med 2012;29:682 689; 2. Carver C. Diabetes Educ 2006;32:910 917; 3. Giugliano et al. Diab Care. 2011;34:510 517

IDegLira is not marketed in Spain DUAL trials Hypoglycaemia IDegLira Placebo (DUAL IV) IGlar U100 (DUAL V and IX) Insulin degludec (DUAL I and II) Liraglutide (DUAL I)/GLP-1 RA (DUAL III) IGlar U100 + IAsp (DUAL VII) 10.0 9.0 8.2 Rates of hypoglycaemia 8.0 7.0 (events per PYE) 6.0 5.1 5.0 3.5 4.0 2.8 2.8 2.6 3.0 2.2 1.8 1.5 2.0 1.4 1.1 0.9 0.8 1.0 0.4 0.2 0.2 0.1 0.0 2WT 1WT DUAL I DUAL I ext. DUAL IV DUAL IV DUAL VI DUAL VI DUAL IX DUAL IX DUAL III GLP-1 RA switch DUAL II DUAL II DUAL V DUAL V DUAL VII DUAL VII DUAL III Basal insulin switch Add to OAD(s) 1WT, once-weekly titration; 2WT, twice-weekly titration; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IAsp;, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; OAD, oral anti-diabetic drug Gough et al. Diabetes Obes Metab 2015;17:965 73; Buse et al. Diabetes Care 2014;37:2926 2933; Linjawi et al. Diabetes Ther 2017;8:101 114; Rodbard et al. Diabet Med 2017;34:189 196; Lingvay et al. JAMA 2016;315:898 907; Harris et al. Diabetes Obes Metab 2017;19:858 865; Billings et al. Diabetes Care 2018;41:1009 1016; Philis-Tsimikas et al.Diabetes Obes Metab 2019;21:3199 1408

IDegLira is not marketed in Spain Common barriers to insulin initiation and intensification Weight gain2 Complexity1 Hypoglycaemia1 More than half of T2D patients on basal insulin are not at target HbA1c3 T2D, type 2 diabetes 1. Peyrot et al. Diabet Med 2012;29:682 689; 2. Carver C. Diabetes Educ 2006;32:910 917; 3. Giugliano et al. Diab Care. 2011;34:510 517

IDegLira is not marketed in Spain DUAL trials Body weight IDegLira Placebo (DUAL IV) IGlar U100 (DUAL V and IX) Insulin degludec (DUAL I and II) Liraglutide (DUAL I)/GLP-1 RA (DUAL III) IGlar U100 + IAsp (DUAL VII) 4.0 Change in body weight (kg) 2.6 3.0 2.3 2.0 2.0 1.8 2.0 1.0 0.5 0.0 0.0 -0.1 -0.4 -1.0 -0.8 -0.9 -1.0 -1.0 -1.4 -2.0 -2.0 -3.0 -2.7 -3.0 -4.0 2WT DUAL VI 1WT -5.0 DUAL IV DUAL VII DUAL I ext. DUAL IX DUAL III DUAL II DUAL V GLP-1 RA switch Basal insulin switch Add to OAD(s) 1WT, once-weekly titration; 2WT, twice-weekly titration; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IAsp;, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; OAD, oral anti-diabetic drug Gough et al. Diabetes Obes Metab 2015;17:965 73; Buse et al. Diabetes Care 2014;37:2926 2933; Linjawi et al. Diabetes Ther 2017;8:101 114; Rodbard et al. Diabet Med 2017;34:189 196; Lingvay et al. JAMA 2016;315:898 907; Harris et al. Diabetes Obes Metab 2017;19:858 865; Billings et al. Diabetes Care 2018;41:1009 1016; Philis-Tsimikas et al.Diabetes Obes Metab 2019;21:3199 1408

IDegLira is not marketed in Spain Common barriers to insulin initiation and intensification Weight gain2 Complexity1 Hypoglycaemia1 More than half of T2D patients on basal insulin are not at target HbA1c3 T2D, type 2 diabetes 1. Peyrot et al. Diabet Med 2012;29:682 689; 2. Carver C. Diabetes Educ 2006;32:910 917; 3. Giugliano et al. Diab Care. 2011;34:510 517

IDegLira is not marketed in Spain DUAL VII Trial design IDegLira + metformin (n=252) Trial information: Open label Non-inferiority Treat-to-target Patients with T2D (N=506) IGlar U100 + IAsp ( 4 times) + metformin (n=254) 1:1 Randomisation Screening End of trial 0 26 2 Week Basal bolus IDegLira 1pen1 1injection1 1SMBG test2 2 Daily regimen pens1 Daily regimen F M W T T S S BREAKFAST 2-5 2-5 F M W T T S S injections2 LUNCH EVENING DINNER SMBG test2 Number of injections and SMBG tests are based on the number of meals IAsp, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; SMBG, self-monitored blood glucose; T2D, type 2 diabetes 1. Billings et al. Diabetes Care 2018;41:1009 1016; 2. Owens et al. Diabetes Prim Care 2004;6:8 16

IDegLira is not marketed in Spain DUAL VII HbA1c over time 8.5 69 IDegLira (n=252) IGlar U100 + IAsp (n=254) 8.0 64 HbA1c (mmol/mol) 7.5 58 HbA1c (%) 7.0 53 6.5 48 6.0 42 0 0.0 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) IDegLira IGlar U100 + IAsp ETD [95% CI] 0.02 [ 0.16; 0.12] HbA1c (%) 1.49 1.48 p<0.0001 for test of non-inferiority by 0.3% ETD is based on LSMeans from full analysis set, using mixed model for repeated measurement. The dashed lines denote the ADA/EASD HbA1c target <7.0% and AACE HbA1c 6.5% CI, confidence interval; ETD, estimated treatment difference; IAsp, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; LSMean, least squares mean Figure sourced from: Billings et al. Diabetes Care 2018;41:1009 1016 (Figure 2A); Billings et al. Diabetes 2017;66(Suppl. 1):A36

IDegLira is not marketed in Spain DUAL VII Key clinical findings Confirmed hypoglycaemia Weight HbA1c IDegLira IGlar U100 + IAsp IDegLira IGlar U100 + IAsp ERR: 0.11 [0.08; 0.17]95% CI, p<0.0001 Change in body weight (kg) 0.0 3 10 Change in HbA1c (%) Hypoglycaemia rate 2.64 2 8 -0.5 (episodes/yr) 8.17 1 6 -1.0 0 4 -1.46 -1.48 -0.93 -1.5 2 -1 1.07 ETD: ETD: 0.02% [ 0.16; 0.12]95% CI, p<0.0001 for non-inferiority* -2.0 0 -2 3.57 kg [ 4.19; 2.95]95% CI, p<0.0001 IGlar U100 + IAsp IDegLira Baseline HbA1c EOT HbA1c 8.2% 6.7% 8.2% 6.7% *Test against non-inferiority limit of 0.3%; Severe or BG-confirmed symptomatic: an episode that is severe according to the ADA classification or BG-confirmed by a plasma glucose value <3.1 mmol/L (<56 mg/dL) with symptoms consistent with hypoglycaemia CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference; ERR, estimated rate ratio; IAsp, insulin aspart; IGlar U100, insulin glargine U100; PYE, patient-years of exposure Billings et al. Diabetes Care 2018;41:1009 1016

IDegLira is not marketed in Spain DUAL VII Percentage of patients receiving 0, 1, 2 or 3 bolus injections at Week 26 (BB arm) 7.8% Number of bolus injections 0 (n=3) 24.3% 67% of patients required 3 and 24% of patients required 2 bolus injections 1 (n=18) 2 (n=56) 3 (n=153) Each bolus injection required an SMBG reading and a decision regarding the dose Data are based on the full analysis set. BB, basal bolus; IDegLira, insulin degludec/liraglutide; SMBG, self-monitored blood glucose Miller et al. Diabetes Obes Metab 2019; doi: 10.1111/dom.13851

IDegLira is not marketed in Spain Impact of multiple daily injections Patients perception of treatment burden versus number of daily injections from a self-administered, mailed survey 6 5 4.8 4.4 4 Perceived burden (0 to 6) 3.9 3.5 3 2 1 0 + Insulin twice + 3 SMBGs daily Insulin 3 4 times daily Insulin once daily Insulin twice daily The scale ranges from 0 (do not dislike at all) to 6 (dislike very much) Adapted from Vijan et al. J Gen Intern Med 2005;20:479 482

IDegLira is not marketed in Spain DUAL VII Number of insulin dose adjustments required during 26 weeks of treatment 350 IDegLira (n=252) IGlar U100 + IAsp (n=253) 300 250 200.1 Mean (SD) number of insulin dose adjustments during trial 200 150 100 17.1 50 16.6 0 0 Basal insulin Bolus insulin There were a similar number of basal dose adjustments in patients treated with IDegLira vs IGlar U100, despite IDegLira being initiated at 16 U, whereas IGlar U100 was titrated from the pre-trial basal dose (mean 33 U) Data are mean (SD) based on the safety analysis set. IAsp, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; SD, standard deviation Miller et al. Diabetes Obes Metab 2019; doi: 10.1111/dom.13851

IDegLira is not marketed in Spain Insulin titration in clinical practice Almost 50% of patients with T2D who start basal insulin do not achieve HbA1c targets1 and there are several key reasons for titration inertia A European survey of HCPs and basal insulin-treated patients found: 25% 59% 18% 38% of patients uncontrolled after 27 months only increased dose by <10 U since initiation2 of patients were concerned that a dose increase means disease is getting worse3 of patients were concerned about injecting too much insulin3 of patients thought treatment is a burden/not a priority3 HCP, healthcare professional; T2D, type 2 diabetes; U, units 1. Stark Casagrande et al. Diabetes Care 2013;36:2271 2279; 2. Berard et al. EASD 2016; poster 910; Berard et al. Diabetes Obes Metab 2018;20:301 308

IDegLira is not marketed in Spain DUAL VII Total daily insulin dose over time IDegLira total insulin dose (n=252) IGlar U100 + IAsp total insulin dose (n=253) 100 84.1 U BB total insulin dose 80 Insulin dose (units) ETD: 44.50 U [ 48.30; 40.71]95% CI p<0.0001 60 40 40.4 U IDegLira total insulin dose 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) ETD is based on observed data using MMRM with treatment, region and visit as factors and insulin dose at screening and baseline HbA1c as covariates BB, basal bolus; CI, confidence interval; ETD, estimated treatment difference; IAsp, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; MMRM, mixed model for repeated measurement; U, units Billings et al. Diabetes Care 2018;41:1009 1016

IDegLira is not marketed in Spain DUAL VII Basal bolus components of insulin dose over time Bolus insulin (IAsp) component dose of BB IDegLira total insulin dose (n=252) IGlar U100 + IAsp total insulin dose (n=253) 100 Basal insulin (IGlar U100) component dose of BB 84.1 U BB total insulin dose 80 Insulin dose (units) ETD: 44.50 U [ 48.30; 40.71]95% CI p<0.0001 60 40 40.4 U IDegLira total insulin dose 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) ETD is based on observed data using MMRM with treatment, region and visit as factors and insulin dose at screening and baseline HbA1c as covariates BB, basal bolus; CI, confidence interval; ETD, estimated treatment difference; IAsp, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; MMRM, mixed model for repeated measurement; U, units Billings et al. Diabetes Care 2018;41:1009 1016

IDegLira is not marketed in Spain DUAL VII Percentage of patients achieving HbA1c <7.0% and composite endpoints IDegLira (n=252) IGlar U100 + IAsp (n=254) 100 Odds ratio: 0.91 [0.62; 1.33]95% CI, NS Proportion of patients Odds ratio: 2.58 [1.78; 3.74]95% CI* achieving target (%) 80 Odds ratio: 4.46 [2.89; 6.89]95% CI* Odds ratio: 10.39 [5.76; 18.75]95% CI* 60 66.0 67.0 57.6 40 43.3 38.2 33.5 20 6.4 15.5 0 HbA1c <7.0% HbA1c <7.0%, no weight gain HbA1c <7.0%, no hypoglycaemiaa HbA1c <7.0%, no hypoglycaemiaa and no weight gain %, Based on observed data. *Statistically significant difference (in favour of IDegLira). aSevere or BG-confirmed symptomatic hypoglycaemia was based on hypoglycaemic episodes during a patient s last 12 weeks of treatment BG, blood glucose; CI, confidence interval; IAsp, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; NS, non-significant Billings et al. Diabetes Care 2018;41:1009 1016

IDegLira is not marketed in Spain A common concern when initiating GLP-1 RAs are GI side effects GI side effects, particularly nausea, are the most frequently reported adverse events in patients treated with GLP-1 RAs1,2 However, these side effects are generally transient, occurring mainly in the initial weeks of treatment3 GLP-1 RA, glucagon-like peptide-1 receptor agonist; GI, gastrointestinal; IDegLira, insulin degludec/liraglutide 1. Nauck et al. Diabetes Care 2009;32:84 90; 2. Balena et al. Diabetes Obes Metab 2013;15:485 502; 3. Garber. Diabetes Care 2011;34(Suppl. 2):S279 S284

IDegLira is not marketed in Spain DUAL I ext., II and III Nausea 12 DUAL I extension1 Open label 10 After OAD Patients (%) IDegLira (n=825) Degludec (n=412) Liraglutide (n=412) 8 6 4 2 0 Week 0 4 8 12 16 20 24 28 32 36 40 44 48 52 DUALII2 IDegLira (n=199) Degludec (n=199) 12 Open label Double blind DUAL III3 After GLP-1 RA 12 After insulin 10 Patients (%) IDegLira (n=291) GLP-1 RA (n=145) 10 Patients (%) 8 8 6 6 4 4 2 2 0 0 Week Week 0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28 GLP-1 RA, glucagon-like peptide-1 receptor agonist; IDegLira, insulin degludec/liraglutide; OAD, oral anti-diabetic drug 1. Gough et al. Diabetes Obes Metab 2015;17:965 73; 2. Buse et al. Diabetes Care 2014;37:2926 2933; 3. Linjawi et al. Diabetes Ther 2017;8:101 114

IDegLira is not marketed in Spain What about patient-reported outcomes across the DUAL programme? TRIM-D total score in DUAL III, V, VII, IX IDegLira vs unchanged GLP-1 RA1 IGlar U1002 IDegLira + SGLT2i vs IGlar U100 + SGLT2i4 IDegLira vs IDegLira vs basal bolus therapy3 ETD: 5.0 [2.9; 7.2]95%CI, p<0.001 ETD: 2.8 [0.9; 4.7]95%CI, p=0.003 ETD: 6.5 [4.4; 8.6]95%CI, p<0.0001 ETD: 2.8 [0.8; 4.7]95%CI, p=0.0052 Change in score 10 from baseline 8 6 4 2 0 Baseline score 75.0 73.6 70.9 75.3 73.6 74.6 72.9 75.8 IDegLira GLP-1 RA IDegLira IGlar U100 IDegLira Basal bolus IDegLira IGlar U100 CI, confidence interval; ETD, estimated treatment difference; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; TRIM-D, Treatment- Related Impact Measure Diabetes 1. Linjawi et al. Diabetes Ther 2017;8:101 114; 2. Lingvay et al. JAMA 2016;315:898 907; 3. Miller et al. Diabetes Obes Metab 2019; doi: 10.1111/dom.13851; 4. Brod et al. ADA 2018; Poster 101-LB

IDegLira is not marketed in Spain Real-world evidence with IDegLira EXTRA study design Retrospective data extraction Patients with T2D from 61 clinics in 5 countries (N=611) On glucose- lowering drugs 6 months IDegLira (or other post-switch therapy) other diabetic medication Baseline Inclusion criteria T2D 18 years Minimum data available: HbA1c at baseline and 6 months post-switch 6 months before initiation 3 months 45 days 6 months 45 days 9 months 45 days 12 months 45 days IDegLira initiation Data extraction* Statistical analyses on all safety and effectiveness outcomes were conducted on the EAS (all patients who continued IDegLira treatment for 6 months, n =566) *Where data available at 3-, 9- and 12-month time points. Baseline values were defined as the most recent values during the 6-month period before first prescription of IDegLira Participants were from Germany, UK, Sweden, Austria and Switzerland EAS, effectiveness analysis set Price et al. Diabetes Obes Metab. 2018;20:954 962

IDegLira is not marketed in Spain Real-world evidence with IDegLira EXTRA: change in HbA1c from baseline to 6 months 9.5 8.9% 9.0 8.6% 8.4% 8.3% 8.3% 8.3% 8.5 HbA1c (%) -1.6%* -1.0%* -0.9%* 8.0 -0.9%* -0.6%* -0.7%* 7.5 7.6% 7.6% 7.5% 7.5% 7.4% 7.3% 7.0 6.5 0.0 Overall (n=566) Non-injectable therapy (n=112) GLP-1RA OAD (n=57) Basal OAD (n=109) Insulin MDI OAD (n=153) Insulin + GLP- 1RA OAD (n=135) *p<0.0001. Data based on effectiveness analysis set (EAS) - all patients included in the FAS and having continued IDegLira treatment for at least 6 months after initiation and with at least one measurement of HbA1c at 6 months ( 45 days). Significance assessed using a two-tailed paired t-test GLP-1 RA, glucagon like peptide-1 receptor agonist; MDI, multiple dose insulin injection; n, number of patients with data at both time points; OAD, oral anti-diabetic drugs Price et al. Diabetes Obes Metab 2018;20:954 962

IDegLira is not marketed in Spain Real-world evidence with IDegLira Persistence in Sweden Persistency* of IDegLira at 6 months Change in HbA1c 6 months after initiating treatment with IDegLira 100 9.0 9.0 9.0 6% n=151 0.5 p<0.07 90 Percentage of patients (%) 0.9 p<0.001 80 Change in HbA1c (%) 8.5 84% of patients were persistent at 12 months 8.5 70 60 8.0 8.1 94% n=2281 50 40 7.5 Persistent Non-persistent Persistent (n=919) Non-persistent (n=62) 30 20 7.0 10 0 6.5 0.0 *Patients who collected IDegLira from a pharmacy at least one more time within 6 months after the first collection (index date) and were defined as having 6-month persistency. Patients who collected IDegLira from a pharmacy at least one more time within 6 months after the index date, and at least one more time between the 6 and 12 months after initiation, and were defined as having 12-month persistency IDegLira, insulin degludec/liraglutide; RWE, real-world evidence. Eliasson et al. Diabetes 2019;68(Supplement 1) 1110-P

IDegLira is not marketed in Spain IDegLira improves patient outcomes HbA1c In DUAL I IX, IDegLira decreased mean HbA1c to below 7.0% (6.0 6.9%) IDegLira provided a weight benefit, low risk of hypoglycaemia and low risk of GI adverse events AEs These results were achieved with once-daily injection of IDegLira IDegLira improved TRIM-D total scores Real-world studies demonstrate that a high percentage of patients persist with IDegLira for 6 and 12 months and significantly reduce their HbA1c AE, adverse events; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IDegLira, insulin degludec/liraglutide; TRIM-D, Treatment-Related Impact Measure Diabetes

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