1. UK/TB/0213/0017a February 2013 New treatment options Dr Craig Parkinson

2. UK/TB/0213/0017a February 2013 Normal renal glucose handling 1–3 SGLT, sodium-glucose co-transporter. 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21. SGLT2 Glucose Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule Remaining glucose is reabsorbed by SGLT1 (10%) Minimal to no glucose excretion Glucose filtration

3. UK/TB/0213/0017a February 2013 Dapagliflozin: A novel insulin- independent approach to remove excess glucose Proximal tubule Glucose filtration 1. FORXIGA Summary of Product Characteristics Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule 1 SGLT2 Glucose Dapagliflozin SGLT2 Dapagliflozin Increased urinary glucose excretion

4. UK/TB/0213/0017a February 2013 The benefits of dapagliflozin’s novel mechanism of action Dapagliflozin offers an insulin-independent mechanism that can be used as add-on therapy 1,4 Dapagliflozin inhibition of SGLT2 results in daily urinary glucose excretion of approximately 70g, 2 providing: Significant and sustained HbA 1c reductions versus placebo when added to metformin 1,3 Secondary benefit of weight loss 1 1.Bailey CJ, et al. Lancet 2010;375:2223–33; 2.List JF, et al. Diabetes Care 2009;32:650–7; 3.Bailey CJ, et al. Poster 988-P. Poster presented at 71st Scientific Sessions of the American Diabetes Association, San Diego, California, 24– 28 June, 2011 4.FORXIGA Summary of Product Characteristics

5. UK/TB/0213/0017a February 2013 Dapagliflozin: Reductions in HbA 1c were sustained over 102 weeks Data are mean change from baseline after adjustment for baseline value. Data after rescue are excluded. Analyses were obtained by longitudinal repeated measures analyses. CI, confidence interval. Adapted from Bailey CJ et al. Poster #988-P. Poster presented at 71 st Scientific Sessions of the American Diabetes Association, San Diego, California, June 24 – 28, 2011. Study week –1.2 –0.8 –0.6 –0.4 0.2 0163750637610289 0.0 HbA 1c (%) mean change from baseline 8 24 Primary endpoint –1.0 –0.2 –5 0 –10 Dapagliflozin 10 mg + metformin (Mean baseline HbA 1c 7.92% [63 mmol/mol]) Placebo + metformin (Mean baseline HbA 1c 8.11% [65 mmol/mol]) (n=133) (n=132) HbA 1c (mmol/mol) mean change from baseline +0.02% (0.2 mmol/mol) ( 95% Cl, –0.20 to 0.23%; n=28) –0.78% (–8.5 mmol/mol) (95% Cl, –0.97 to –0.60%; n=57) 0.80% (8.8 mmol/mol) difference

6. UK/TB/0213/0017a February 2013 Dapagliflozin: secondary benefit of weight loss over 102 weeks Weight loss at 24 weeks, with decreased waist circumference is consistent with a reduction of body-fat mass 1 In a separate study, weight loss was mainly attributable to reduction in body fat mass rather than loss of fluid or lean tissue 3 # Adjusted mean change from baseline body weight (kg) 24 weeks (LOCF analysis) 1 –1.70 kg ( n=95) 95% Cl (-2.48 to - 0.91) –2.9 kg (n=133) 95% CI (-3.3 to -2.4 ) –0.9 kg (n=136) 95%CI -1.4 to -0.4 2.0 kg difference p<0.0001 +1.36 kg (n=73) 95% Cl (0.53 to 2.20) 3.1 kg difference p value not calculated Data are mean change from baseline after adjustment for baseline value ( mean baseline weight: dapagliflozin 86.3 kg, placebo 87.7 kg). 24-week data are based on LOCF analysis excluding data after rescue; 102-week data are based on longitudinal repeated measures analysis and include data after rescue. # As measured by dual energy absorptiometry at 24 weeks 1. Bailey CJ, et al. Lancet 2010;375:2223–33; 2. Bailey CJ, et al. Poster 988-P. Poster presented at 71st Scientific Sessions of the American Diabetes Association, San Diego, California, June 24–28, 2011; 3. Bolinder J, et al. J Clin Endocrinol Metab 2012;97:1020–31. 102 weeks (repeated measures analysis) 2 Dapagliflozin 10 mg + metformin Dapagliflozin 10 mg + metformin Placebo + metformin Placebo + metformin Adapted from Bailey CJ, et al. (2010) & Bailey CJ, et al. (2011)

7. UK/TB/0213/0017a February 2013 Reductions in HbA 1c with insulin + dapagliflozin compared with insulin + placebo at 24 weeks 1. Wilding J, et al. Ann Intern Med 2012;156:405 – 415. 2. FORXIGA™. Summary of product characteristics. Adapted from Wilding J, et al. 2012 Last observation carried forward (LOCF). Data are adjusted mean change from baseline. Mean HbA 1c at baseline were 8.47% (69 mmol/mol) for insulin + placebo and 8.57% (70 mmol/mol) for insulin + dapagliflozin 10mg. Consider a reduction in insulin dose on commencement of dapagliflozin to reduce the risk of hypoglycaemia 2 Dapagliflozin 10 mg + insulin Placebo + insulin –0.96% (–10.5 mmol/mol) (n=194) –0.39% (–4.3 mmol/mol) (n=193) 0.57% (6.2 mmol/mol) difference (95% CI, – 0.72 to – 0.42%) p<0.001 -10 -5 0

8. UK/TB/0213/0017a February 2013 Uptitration of insulin dosing is less pronounced in patients treated with insulin + dapagliflozin compared with insulin + placebo ± oral antidiabetic drugs Change in total daily insulin dose (units) from baseline 1 : At 24 weeks placebo + insulin – 8% increase dapagliflozin + insulin – 1.5% decrease At 48 weeks placebo + insulin – 14% increase dapagliflozin + insulin – 1% decrease Patients needing rescue therapy or withdrawn from study for not achieving glycaemic targets: 1 Placebo + insulin – 42.8% dapagliflozin 10mg + insulin – 15.3% Baseline mean daily insulin dose (units): Insulin + placebo = 73.7 Insulin + dapagliflozin 10mg = 78.0 Consider a reduction in insulin dose on commencement of dapagliflozin to reduce the risk of hypoglycaemia 2 1. Wilding JPH et al. Ann Intern Med 2012;156:405 – 415. 2. FORXIGA™. Summary of product characteristics.. Dapagliflozi n 190

9. UK/TB/0213/0017a February 2013 1. Ferrannini E et al. Diabetes Care 2010;33:2217–2224. 2. Bailey CJ et al. Lancet 2010;375:2223–2233. 3. Strojek K et al. Diabetes Obes Metab 2011;13:928–938. 4. Wilding JPH et al. Ann Intern Med 2012;156:405–415. Dapagliflozin: Consistent reduction in HbA 1c at Week 24 across studies Baseline HbA 1c : 7.91%; 63 mmol/mol Mean change in HbA 1c (%) –0.23 (-3 mmol/mol) –0.89* (-10 mmol/mol) –0.84* (-9 mmol/mol) –0.30 (-3 mmol/mol) –0.82* (-9 mmol/mol) –0.13 (-1 mmol/mol) –0.96* (-10 mmol/mol) –0.39 (-4 mmol/mol) Baseline HbA 1c : 8.05%; 64 mmol/mol Baseline HbA 1c : 8.11%; 65 mmol/mol Baseline HbA 1c : 8.53%; 70 mmol/mol Add-on to a SU 3 Add-on to metformin 2 Monotherapy 1 Add-on to insulin 4 These data are taken from different studies and the results should not be compared across studies. *Statistically significant vs. placebo using Dunnett’s correction. SU, sulphonylurea. Dapagliflozin (10 mg) Placebo p<0.0001 p<0.001

10. UK/TB/0213/0017a February 2013 1.1 Dapagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if it is used as described for dipeptidyl peptidase ‑ 4 (DPP ‑ 4) inhibitors in Type 2 diabetes: the management of type 2 diabetes (NICE clinical guideline 87).Type 2 diabetes: the management of type 2 diabetes 1.2 Dapagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes. 1.3 Dapagliflozin in a triple therapy regimen in combination with metformin and a sulfonylurea is not recommended for treating type 2 diabetes, except as part of a clinical trial. NICE TA288 http://publications.nice.org.uk/dapagliflozin-in- combination-therapy-for-treating-type-2-diabetes- ta288

11. UK/TB/0213/0017a February 2013 Tresiba ® – A new basal insulin for adult patients with type 1 and type 2 diabetes

12. UK/TB/0213/0017a February 2013 Half-life of insulin degludec is twice as long as that of insulin glargine Insulin degludecInsulin glargine 0.4 U/kg0.6 U/kg0.8 U/kg0.4 U/kg0.6 U/kg0.8 U/kg Half-life (hours)25.927.023.911.814.011.9 Mean half-life25.412.5 *Insulin glargine was undectable after 48 hours Results from patients with type 1 diabetes IDeg, insulin degludec; IGlar, insulin glargine Heise et al. Diabetologia 2011;54(Suppl. 1):S425 * IDeg 0.8 U/kg IGlar 0.8 U/kg

13. UK/TB/0213/0017a February 2013 70 40 HbA 1c (mmol/mol) 65 0 35 50 55 60 75 45 Insulin-naïve T2D: HbA 1c and FPG over time BEGIN ® ONCE LONG Mean±SEM; full analysis set (FAS); last observation carried forward (LOCF) Comparisons: estimates adjusted for multiple covariates Zinman et al. Diabetes Care 2012;35:2464–71 0.0 Treatment difference: non-inferior Time (weeks) Treatment difference: –0.43 mmol/L, p<0.05 0.0 Time (weeks) IDeg OD (n=773) IGlar OD (n=257) 26

14. UK/TB/0213/0017a February 2013 Insulin-naïve T2D: confirmed hypoglycaemia BEGIN ® ONCE LONG Severe hypoglycaemia: IDeg, 0.00 events/PYE; IGlar, 0.02 events/PYE SAS; LOCF; Comparisons: estimates adjusted for multiple covariates PYE, patient-years of exposure Zinman et al. Diabetes Care 2012; 35:2464–71 IDeg OD (n=766) IGlar OD (n=257) 18% lower rate with IDeg (ns) Time (weeks) IDeg: 1.52 events/PYE IGlar: 1.85 events/PYE

15. UK/TB/0213/0017a February 2013 Insulin-naïve T2D: nocturnal confirmed hypoglycaemia BEGIN ® ONCE LONG SAS; LOCF Comparisons: estimates adjusted for multiple covariates Zinman et al. Diabetes Care 2012; 35:2464–71 36% lower rate with IDeg, p<0.05 Time (weeks) IDeg: 0.25 events/PYE IGlar: 0.39 events/PYE IDeg OD (n=766) IGlar OD (n=257)

16. UK/TB/0213/0017a February 2013 70 40 HbA 1c (mmol/mol) 65 0 35 50 55 60 75 45 Treatment difference: non-inferior Basal–bolus in T2D: HbA 1c and FPG over time BEGIN ® BB T2D IDeg OD + IAsp (n=744) IGlar OD + IAsp (n=248) Mean±SEM; FAS; LOCF; IAsp, insulin aspart Comparisons: estimates adjusted for multiple covariates Garber et al. Lancet 2012;379:1498–507 Treatment difference: –0.29 mmol/L (ns) Time (weeks) 0.0 26

17. UK/TB/0213/0017a February 2013 Basal–bolus in T2D: confirmed hypoglycaemia BEGIN ® BB T2D IDeg OD + IAsp (n=753) IGlar OD + IAsp (n=251) Severe hypoglycaemia: IDeg, 0.06 events/PYE; IGlar, 0.05 events/PYE SAS; LOCF; Comparisons: estimates adjusted for multiple covariates Garber et al. Lancet 2012;379:1498–507 18% lower rate with IDeg, p=0.0359 Time (weeks) IDeg: 11.09 events/PYE IGlar: 13.63 events/PYE

18. UK/TB/0213/0017a February 2013 Basal–bolus in T2D: confirmed nocturnal hypoglycaemia BEGIN ® BB T2D IDeg OD + IAsp (n=753) IGlar OD + IAsp (n=251) SAS; LOCF Comparisons: estimates adjusted for multiple covariates Garber et al. Lancet 2012; 379:1498–507 25% lower rate with IDeg, p=0.0399 Time (weeks) IDeg: 1.39 events/PYE IGlar: 1.84 events/PYE

19. UK/TB/0213/0017a February 2013 Based on the long duration of action and flat profile insulin degludec can be administered at any time of the day

20. UK/TB/0213/0017a February 2013 Flexible vs Fixed dosing: nocturnal confirmed hypoglycaemia BEGIN ® FLEX T2D 23% lower rate with IDeg Flexible than with IGlar (ns) 18% higher rate with IDeg Flexible than with IDeg Fixed (ns) SAS; LOCF Comparisons: estimates adjusted for multiple covariates Birkeland et al. IDF 2011:P-1443; Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(Suppl. 1):S423; Atkin et al. Diabetologia 2011;54(Suppl. 1):S53; Meneghini et al. Diabetes 2011;60(Suppl. 1A):LB10 IDeg Flexible OD (n=230) IDeg Fixed OD (n=226) IGlar OD (n=229) IDeg Flexible: 0.63 events/PYE IDeg Fixed: 0.56 events/PYE IGlar: 0.75 events/PYE

21. UK/TB/0213/0017a February 2013 Insulin degludec is available in two strengths, what you see is what you get The insulin degludec U200 pen: Ability to deliver up to 160U in one injection No dose conversion if transferring from U100 (what you see is what you get) Provides a 50% lower injection volume for patients requiring higher insulin doses U100 pen Up to 80U in 1U increments U200 pen Up to 160U in 2U increments Tresiba ® SmPC, Novo Nordisk, January 2013

22. UK/TB/0213/0017a February 2013 UK NHS spend on basal insulins during 2012 (IMS data) 1 Only 8.3% of the basal insulin spend nationally is on human NPH insulin 1 If all prescriptions dispensed for analogue insulin between 2000 and 2009 had used a human insulin alternative, the NHS would have saved an estimated £625 million 2 NPH=neutral protamine Hagedorn 1.DATA ON FILE: UK NHS spend on basal insulins during 2012 2.Holden SE et al (2011) BMJ Open 1: e000258 )

23. UK/TB/0213/0017a February 2013 Not Discussed First choice gliptin – sitagliptin First choice GLP-1 – Lixisenatide Use of GLP-1 therapy with basal insulin therapy