Intensifying Treatment Beyond Monotherapy in T2DM: Where Do Newer Therapies Fit?

Transcription

1 Intensifying Treatment Beyond Monotherapy in T2DM: Where Do Newer Therapies Fit? Vanita R. Aroda, MD Scientific Director & Physician Investigator MedStar Community Clinical Research Center MedStar Health Research Institute Associate Professor of Medicine Endocrinology, Diabetes, and Metabolism Georgetown University School of Medicine June, 2017

2 Disclosures All activities have been conducted through my employer (MedStar Health Research Institute): Research activities (clinical trials): AstraZeneca, Boehringer Ingelheim, Calibra, Eisai, Novo Nordisk, Sanofi, Takeda Consultative activities: ADA, Adocia, Endocrine Society, Novo Nordisk, Sanofi, Tufts

3 Audience Question: What proportion of patients in your daily practice will require additional therapy after metformin within 5-6 years? Choose one A.0 25% B.25 50% C.50 75% D %

4 Patients failing monotherapy with metformin (%) Failure of maintaining stable glycemic control on monotherapy with metformin Clinical practice: 17%/year, decreased to ~12%/year with early initiation or lower baseline A1c Age, duration, and A1c at initiation were the only factors that predicted secondary failure Treatment-naïve Category patients 1 Dx ~4.4 years Follow up 5.5 years 1 Treatment-naïve patients Dx ~ 2 years Follow up 5 years 2 Treatment-naïve patients (UKPDS) Follow up 6 years 3 Metformin-treated patients months (KPNW) Follow up 2-5 years mean 2 years, 2 months 4 1. Ekström N et al. BMJ 2015;3:e e000068; 2. Kahn SE et al. N Engl J Med 2006;355: ; 3. Turner RC et al. JAMA 1999;281: ; 4. Brown JB et al. Diabetes Care 2010;33:

5 Going back 10 years to 2007

6 Case study (2007): 52-year-old female Patient characteristics Diabetes history Glucose-lowering therapy HbA 1c 8.1% Weight T2D for 8 years Metformin 1500 mg/day 99.4 kg BMI 34.2 kg/m 2 BMI, body mass index; HbA 1c, glycosylated haemoglobin; T2D, type 2 diabetes

7 Diabetes treatment options for our patient: Older therapies" Metformin Thiazolidinediones Human insulin 1950s 1960s 1970s 1980s 1990s 2000s 2010s Sulfonylureas Insulin analogues; AGIs; glinides AGI, alpha-glucosidase inhibitor

8 Audience Question: It is 2007 ( older therapies ). How would you intensify treatment in this patient to improve glycaemic control? T2DM 8 years, HbA 1c 8.1%, weight 99.4 kg, BMI 34.2 kg/m 2 Choose one A.Sulfonylurea B.Insulin analogue C.Thiazolidinedione D.Alpha glucosidase inhibitor E.Glinide BMI, body mass index; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated haemoglobin; SGLT-2i, sodium-glucose co-transporter-2 inhibitor; T2D, type 2 diabetes

9 Paradigm shifts in the last decade Glucose control matters Get to goal safely Treat for the long run

10 Adjusted incidence per 1000 person-years (%) 2000: The lower the glycaemia, the lower the risk for complications, without a threshold 80 Myocardial infarction Microvascular endpoints Updated mean HbA 1c concentration (%) HbA 1c, glycosylated haemoglobin UKPDS 35. BMJ 2000;321:

11 2009: Intensive glycaemic treatment reduces cardiovascular outcomes, no mortality benefit Myocardial infarction Number of events (annual event rate, %) Trials More intensive Less intensive HbA 1c (%) Favours more intensive Favours less intensive Hazard ratio (95% CI) Myocardial infarction ACCORD 198 (1.18) 245 (1.51) ( ) ADVANCE 310 (1.18) 337 (1.28) ( ) UKPDS 150 (0.20) 76 (1.40) ( ) VADT 72 (1.65) 87 (1.99) ( ) Overall ( ) (Q=2.25, p=0.52, I 2 =0.0%) CI, confidence interval; HbA 1c, glycosylated haemoglobin Turnbull FM et al. Diabetologia 2009;52: Hazard ratio (95% CI)

12 2009: Intensive glycaemic treatment reduces cardiovascular outcomes, no mortality benefit All-cause mortality Number of events (annual event rate, %) Trials More intensive Less intensive HbA 1c (%) Favours more intensive Favours less intensive Hazard ratio (95% CI) All-cause mortality ACCORD 257 (1.41) 203 (1.14) ( ) ADVANCE 498 (1.86) 533 (1.99) ( ) UKPDS 123 (0.13) 53 (0.25) ( ) VADT 102 (2.22) 95 (2.06) ( ) Overall ( ) (Q=5.71, p=0.13, I 2 =47.5%) CI, confidence interval; HbA 1c, glycosylated haemoglobin Turnbull FM et al. Diabetologia 2009;52: Hazard ratio (95% CI)

13 Paradigm shifts in the last decade Glucose control matters Get to goal safely Treat for the long run

14 Percent patients, % Barriers to achieving treatment goals Target HbA 1c (%) <6.0 HbA 1c achieved (%) 6.4 ACCORD intensive therapy 1 Hypoglycaemia requiring assistance vs standard (% of patients) Weight gain >10 kg since baseline vs standard (%) 16.2 vs 5.1, p< vs 14.1, p< Exposure to prescribed glucose-lowering medication Secretagogue Thiazolidinedione Any insulin HbA 1c, glycosylated haemoglobin 1. Gerstein HC et al. N Engl J Med 2008;358: Intensive therapy Standard therapy

15 Limitations of older therapies Difficulty in achieving glycemic targets Unacceptable level of weight gain Significantly greater hypoglycemia ACCORD: 3X higher risk of hypoglycemia requiring medical assistance VADT: 2X higher risk of hypoglycemia requiring medical assistance

16 Type 2 diabetes in the 21 st century Perhaps the question is no longer how low our glycemic targets should be to prove macrovascular and mortality benefit, but whether we can make a difference if we get there safely.

17 Expansion of diabetes treatment options in the last decade Human insulin Metformin Thiazolidinediones DPP-4is 1950s 1960s 1970s 1980s 1990s 2000s 2010s Sulfonylureas GLP-1 RAs Insulin analogues; AGIs; glinides SGLT-2is AGI, alpha-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT-2i, sodium glucose co-transporter-2 inhibitor

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19 Methodology Reviewed timeline of all currently available FDAapproved medications for the treatment of type 2 diabetes Reviewed trials listed in clinicaltrials.gov as of August 10, 2016 that met the following criteria: Published phase 3 or phase 4 prospective, randomized interventional studies of current FDA-approved pharmacotherapy for the treatment of T2DM Therapies evaluated: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) Dipeptidyl peptidase-4 (DPP-4) inhibitors Sodium-glucose co-transporter 2 (SGLT2) inhibitors U.S. as a site Study population represented treatment intensification beyond monotherapy Kuhn A Aroda VR. Curr Cardiol Rep 2017

20 Kuhn A Aroda VR. Curr Cardiol Rep 2017

21 Just tell me which one I should choose! Kuhn A Aroda VR. Curr Cardiol Rep 2017

22 Summary of clinical trial evidence of efficacy of DPP-4 Inhibitors in treatment intensification for T2DM Clinical Trials Study Number NCT Comparators SITA 100 mg QD (n=453) PBO (n=224) Baseline HbA1c & FPG 8.0% mg/dl Length (1 o outcome) Change in A1c (%) 24 weeks SITA: PBO: Change in Body Weight (kg) No differences in weight Hypoglycemia No differences in hypoglycemia NCT SITA 100 mg QD (n=96) PBO (n=94) % mg/dl 30 weeks 18 weeks: SITA: PBO: weeks: SITA: PBO: 0.04 No increase in weight No increase in hypoglycemia NCT LIRA 1.8 mg QD (n=218) LIRA 1.2 mg QD (n=221) SITA (n=219) 8.5% 180 mg/dl 26 weeks LIRA 1.8 mg: LIRA 1.2 mg: SITA: LIRA 1.8 mg: LIRA 1.2 mg: SITA: NCT Oral Strategy: SITA 100 mg QD (n=326), then GLIM if needed, Injectable Strategy: LIRA 1.2 mg/day (n=327), then uptitrate to 1.8 mg if needed % mg/dl 26 weeks Oral: -1.3 Injectable: -1.4 Greater hypoglycemia in oral strategy (with sulfonylurea) NCT EXEN 2mg once weekly (n=160) Vs SITA 100 mg QD (n=166) Vs PIO 45 mg QD (n=165) 8.5% 164 mg/dl 26 week EXEN: -1.5 SITA: -0.9 PIO: -1.2 EXEN: -2.3 SITA: -0.8 PIO: 2.8 low, similar NCT ALB once weekly 30 mg, titratable to 50 mg (mean dose 40.5 mg) (n=302), SITA 100 mg QD (n=302), GLIM 2 mg, titratable to 4 mg (mean dose 3.1 mg), QD (n=307), PBO (n=101) 8.1% - 8.2%, mg/dl 104 weeks ALB: SITA: GLIM: PBO: 0.27 ALB: SITA: GLIM: 1.17 PBO: ALB: 3% SITA: 1.7% GLIM: 17.9% PBO: 4% Kuhn A Aroda VR. Curr Cardiol Rep 2017

23 Clinical Trials Study Number Comparators Baseline HbA1c & FPG Length (1 o outcome) Change in A1c (%) Change in Body Weight (kg) Hypoglycemia NCT GLAR (n=250) SITA 100mg QD (n=265) 8.5% mg/dl 24 weeks GLAR: SITA: GLAR: 0.44 SITA: GLAR: 4.21 events per patientyear SITA: 0.50 events per patient-year NCT SAXA 2.5 mg twice daily (n=74), PBO (n=86) %, mg/dl 12 weeks SAXA: PBO: SAXA: PBO: SAXA: 5.4% PBO: 1.2% NCT SAXA 2.5 mg QD (n=192) SAXA 5 mg QD (n=191) SAXA 10 mg QD (n=181) PBO (n=179) 8.0% 176 mg/dl 24 weeks SAXA 2.5: SAXA 5: SAXA 10: PBO: 0.13 No difference compared to PBO No difference compared to PBO 4-year safety follow up with no increase in hypoglycemia or new safety concerns [100] NCT SAXA 5 mg QD (n=138) Uptitration MET to 2000 mg METXR QD (n=144) % 163 mg/dl 18 weeks SAXA: -0.8 Uptitrated METXR: SAXA: 0.4 Uptitrated METXR: -0.5 SAXA: 3.6% Uptitrated METXR: 1.4% NCT SAXA 5 mg/day + DAPA 10 mg/day (n=179), SAXA 5 mg/day + PBO (n=176), DAPA 10 mg/day + PBO (n=179) 8.9% mg/dl 24 weeks SAXA + DAPA: -1.5 SAXA: -0.9 DAPA: -1.2 SAXA + DAPA: -2.1 SAXA: 0.0 DAPA: -2.4 Low (1%) similar rates of hypoglycemia; no major hypoglycemia NCT ALO 12.5 mg QD (n=213), ALO 25 mg QD (n=210), PBO (n=104) 7.9-8% mg/dl 26 weeks ALO 12.5 mg: -0.6 ALO 25 mg: -0.6 PBO: -0.1 No significant difference in hypoglycemia NCT ALO 12.5 mg QD (n=880), ALO 25 mg QD (n=885) GLIP 5mg, titratable to 20 mg (mean final dose 5.2 mg) (n=874) 7.6% 104 weeks ALO 12.5mg: ALO 25mg: GLIP: ALO 12.5 mg: ALO 25 mg: GLIP: 0.95 ALO 12.5mg: 2.5% ALO 25 mg: 1.4% GLIP: 23.2% NCT LINA 5 mg QD (n=524) PBO (n=177) 8.1% 169 mg/dl 24 weeks LINA: PBO: 0.15 LINA: 0.6% PBO: 2.8% NCT LINA 5 mg QD (n=777), GLIM 1-4 mg QD (n=775) 7.7% mg/dl 104 weeks LINA: GLIM: LINA: -1.4 GLIM: 1.3 LINA: 7% GLIM: 36% NCT EMPA 25 mg/lina 5 mg QD (n=137), EMPA 10 mg/lina 5 mg QD (n=136), EMPA 25 mg QD (n=141), EMPA 10 mg QD (n=140), LINA 5 mg (n=132), % mg/dl 24 weeks EMPA 25 mg/lina 5 mg: EMPA 10 mg/lina 5 mg: EMPA 25 mg: EMPA 10 mg: LINA 5 mg: EMPA 25 mg/lina 5 mg: -3.0 EMPA 10 mg/lina 5 mg: -2.6 EMPA 25 mg: -3.2 EMPA 10 mg: -2.5 LINA 5 mg: -0.7 kg Similar adverse events across treatment arms

24 Summary of clinical trial evidence of efficacy of SGLT-2 Inhibitors in treatment intensification for type 2 DM Clinical Trials Study Number Comparators Baseline HbA1c & FPG Length (1 o outcome) Change in A1c (%) Change in Body Weight (kg) Incidence of Hypoglycemia (%) NCT CANA 100mg (CANA100) QD (n=368), CANA 300mg QD (CANA300), (n=367), SITA 100 mg QD, (n=366), SITA + PBO (n=183) 7.9% mg/dl 26 weeks CANA300: CANA100: SITA: at week 52: CANA300: -3.7 CANA100: -3.3 SITA: -1.2 CANA300: 4.7 CANA100: 5.0 SITA: 4.2 SITA/PBO: 2.7 NCT CANA 100mg QD (n=483), CANA 300mg QD (n=485), GLIM (up to 6 mg or 8 mg QD), (n=482) 7.8% mg/dl 52 weeks CANA100: CANA300: GLIM: CANA300: -0.7 CANA100: -0.6 GLIM: +0.7 CANA300: 5 CANA100: 6 GLIM: 34 % NCT DAPA 10mg (DAPA10) QD (n=135), DAPA 5mg (DAPA5) (n=137), DAPA 2.5mg (DAPA2.5) (n=137) PBO (n=137) 8.1% mg/dl 102 weeks DAPA10: DAPA5: DAPA2.5: PBO: 0.02 DAPA10: DAPA5: DAPA2.5: PBO: 1.36 DAPA10: -5.2 DAPA5: DAPA2.5: PBO- 5.8 NCT DAPA10 (n=179), SAXA 5mg(SAXA5), (n=176), DAPA10/SAXA5 (n=179) 8.9% 186 mg/dl 24 weeks DAPA10: SAXA5: DAPA10/SAXA5: DAPA10: -2.4 SAXA5: 0.0 DAPA10/SAXA5: -2.1 DAPA10: 1 SAXA5: 1 DAPA10/SAXA5: 1 NCT EMPA 25mg (EMPA25), (n=141), EMPA 10mg (EMPA10), (n=140), LINA 5mg (LINA5) n=132, EMPA25/LINA5 (n=137), EMPA10/LINA5 (n=136) 7.98% mg/dl 24 weeks EMPA25: EMPA10: LINA5: EMPA25/LINA5: EMPA10/LINA5: EMPA25: -3.2 EMPA10: -2.5 LINA5: -0.7 EMPA25/LINA5: -3.0 EMPA10/LINA5: -2.6 EMPA25: 3.5 EMPA10: 1.4 LINA5: 2.3 EMPA25/LINA5: 3.6 EMPA10/LINA5: 2.2 NCT EMPA25 (n=213), EMPA10 (n=217), PBO (n=207) 7.9% mg/dl 24 weeks EMPA25: EMPA10: PBO EMPA25: EMPA10: PBO: EMPA25: 1.4 EMPA10: 1.8 PBO: 0.5 NCT EMPA25 (n=166), EMPA10 (n=166), SITA (n=56) 7.91% 177.4mg/dl 90 weeks (12 weeks blinded + 78 week openlabel extension) EMPA25: EMPA10: SITA: EMPA25: EMPA10: -3.1 SITA: -0.4 EMPA25: 1.8 EMPA10: 2.4 SITA: 3.6 Kuhn A Aroda VR. Curr Cardiol Rep 2017

25 Summary of clinical trial evidence of efficacy of SGLT-2 Inhibitors in treatment intensification for type 2 DM Clinical Trials Study Number Comparators Baseline HbA1c & FPG Length (1 o outcome) Change in A1c (%) Change in Body Weight (kg) Incidence of Hypoglycemia (%) NCT CANA 100mg (CANA100) QD (n=368), CANA 300mg QD (CANA300), (n=367), SITA 100 mg QD, (n=366), SITA + PBO (n=183) 7.9% mg/dl 26 weeks CANA300: CANA100: SITA: at week 52: CANA300: -3.7 CANA100: -3.3 SITA: -1.2 CANA300: 4.7 CANA100: 5.0 SITA: 4.2 SITA/PBO: 2.7 NCT CANA 100mg QD (n=483), CANA 300mg QD (n=485), GLIM (up to 6 mg or 8 mg QD), (n=482) 7.8% mg/dl 52 weeks CANA100: CANA300: GLIM: CANA300: -0.7 CANA100: -0.6 GLIM: +0.7 CANA300: 5 CANA100: 6 GLIM: 34 % NCT DAPA 10mg (DAPA10) QD (n=135), DAPA 5mg (DAPA5) (n=137), DAPA 2.5mg (DAPA2.5) (n=137) PBO (n=137) 8.1% mg/dl 102 weeks DAPA10: DAPA5: DAPA2.5: PBO: 0.02 DAPA10: DAPA5: DAPA2.5: PBO: 1.36 DAPA10: -5.2 DAPA5: DAPA2.5: PBO- 5.8 NCT DAPA10 (n=179), SAXA 5mg(SAXA5), (n=176), DAPA10/SAXA5 (n=179) 8.9% 186 mg/dl 24 weeks DAPA10: SAXA5: DAPA10/SAXA5: DAPA10: -2.4 SAXA5: 0.0 DAPA10/SAXA5: -2.1 DAPA10: 1 SAXA5: 1 DAPA10/SAXA5: 1 NCT EMPA 25mg (EMPA25), (n=141), EMPA 10mg (EMPA10), (n=140), LINA 5mg (LINA5) n=132, EMPA25/LINA5 (n=137), EMPA10/LINA5 (n=136) 7.98% mg/dl 24 weeks EMPA25: EMPA10: LINA5: EMPA25/LINA5: EMPA10/LINA5: EMPA25: -3.2 EMPA10: -2.5 LINA5: -0.7 EMPA25/LINA5: -3.0 EMPA10/LINA5: -2.6 EMPA25: 3.5 EMPA10: 1.4 LINA5: 2.3 EMPA25/LINA5: 3.6 EMPA10/LINA5: 2.2 NCT EMPA25 (n=213), EMPA10 (n=217), PBO (n=207) 7.9% mg/dl 24 weeks EMPA25: EMPA10: PBO EMPA25: EMPA10: PBO: EMPA25: 1.4 EMPA10: 1.8 PBO: 0.5 NCT EMPA25 (n=166), EMPA10 (n=166), SITA (n=56) 7.91% 177.4mg/dl 90 weeks (12 weeks blinded + 78 week openlabel extension) EMPA25: EMPA10: SITA: EMPA25: EMPA10: -3.1 SITA: -0.4 EMPA25: 1.8 EMPA10: 2.4 SITA: 3.6 Kuhn A Aroda VR. Curr Cardiol Rep 2017

26 Summary of clinical trial evidence of efficacy of SGLT-2 Inhibitors in treatment intensification for type 2 DM Clinical Trials Study Number Comparators Baseline HbA1c & FPG Length (1 o outcome) Change in A1c (%) Change in Body Weight (kg) Incidence of Hypoglycemia (%) NCT CANA 100mg (CANA100) QD (n=368), CANA 300mg QD (CANA300), (n=367), SITA 100 mg QD, (n=366), SITA + PBO (n=183) 7.9% mg/dl 26 weeks CANA300: CANA100: SITA: at week 52: CANA300: -3.7 CANA100: -3.3 SITA: -1.2 CANA300: 4.7 CANA100: 5.0 SITA: 4.2 SITA/PBO: 2.7 NCT CANA 100mg QD (n=483), CANA 300mg QD (n=485), GLIM (up to 6 mg or 8 mg QD), (n=482) 7.8% mg/dl 52 weeks CANA100: CANA300: GLIM: CANA300: -0.7 CANA100: -0.6 GLIM: +0.7 CANA300: 5 CANA100: 6 GLIM: 34 % NCT DAPA 10mg (DAPA10) QD (n=135), DAPA 5mg (DAPA5) (n=137), DAPA 2.5mg (DAPA2.5) (n=137) PBO (n=137) 8.1% mg/dl 102 weeks DAPA10: DAPA5: DAPA2.5: PBO: 0.02 DAPA10: DAPA5: DAPA2.5: PBO: 1.36 DAPA10: -5.2 DAPA5: DAPA2.5: PBO- 5.8 NCT DAPA10 (n=179), SAXA 5mg(SAXA5), (n=176), DAPA10/SAXA5 (n=179) 8.9% 186 mg/dl 24 weeks DAPA10: SAXA5: DAPA10/SAXA5: DAPA10: -2.4 SAXA5: 0.0 DAPA10/SAXA5: -2.1 DAPA10: 1 SAXA5: 1 DAPA10/SAXA5: 1 NCT EMPA 25mg (EMPA25), (n=141), EMPA 10mg (EMPA10), (n=140), LINA 5mg (LINA5) n=132, EMPA25/LINA5 (n=137), EMPA10/LINA5 (n=136) 7.98% mg/dl 24 weeks EMPA25: EMPA10: LINA5: EMPA25/LINA5: EMPA10/LINA5: EMPA25: -3.2 EMPA10: -2.5 LINA5: -0.7 EMPA25/LINA5: -3.0 EMPA10/LINA5: -2.6 EMPA25: 3.5 EMPA10: 1.4 LINA5: 2.3 EMPA25/LINA5: 3.6 EMPA10/LINA5: 2.2 NCT NCT EMPA25 (n=213), EMPA10 (n=217), PBO (n=207) EMPA25 (n=166), EMPA10 (n=166), SITA (n=56) 7.9% mg/dl 7.91% 177.4mg/dl 24 weeks EMPA25: EMPA10: PBO weeks (12 weeks blinded + 78 week openlabel extension) EMPA25: EMPA10: SITA: EMPA25: EMPA10: PBO: EMPA25: EMPA10: -3.1 SITA: -0.4 EMPA25: 1.4 EMPA10: 1.8 PBO: 0.5 EMPA25: 1.8 EMPA10: 2.4 SITA: 3.6 Kuhn A Aroda VR. Curr Cardiol Rep 2017

27 Ferrannini E et al, Diabetes Care 2013; 36:

28 Change in HbA 1c (%) Change in HbA 1c across drug classes Add-on to metformin DPP-4i vs SGLT-2i DPP-4i vs GLP-1 RA Sita vs Cana 1 52 wk Empa vs Sita 2 24 wk DURATION wk LIRA-DPP wk HARMONY wk AWARD wk Baseline HbA 1c (%): n= n= n= n= n= n= n= n= n= n= n= n= n= n= n= *** * 1.3 *** 1.5 *** ** 1.1 ** Sitagliptin 100 mg Canagliflozin 300 mg Empagliflozin 10 mg Empagliflozin 25 mg Exenatide 10 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Albiglutide Dulaglutide 0.75 mg Dulaglutide 1.5 mg *p<0.05; **p<0.001; ***p< DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated haemoglobin; SGLT-2i, sodium-glucose co-transporter-2 inhibitor 1. Lavalle-González FJ et al. Diabetologia 2013;56: ; 2. Roden M et al. Lancet Diabetes Endocrinol 2013;1: ; 3. Bergenstal R et al. Lancet 2010;376: ; 4. Pratley R et al. Int J Clin Pract 2011;65: ; 5. Ahren B et al. Diabetes Care 2014;37: ; 6. Nauck M et al. Diabetes Care 2014;37:

29 Change in weight (kg) Change in body weight across drug classes Add-on to metformin DPP-4i vs SGLT-2i DPP-4i vs GLP-1 RA Sita vs Cana 1 52 wk Empa vs Sita 2 24 wk DURATION wk LIRA-DPP wk HARMONY wk AWARD wk Baseline weight (kg): n= n= n= n= n= n= n= n= n= n= n= n= n= n= n= Sitagliptin 100 mg 3.7 ** *** *** Canagliflozin 300 mg ** *** Empagliflozin 10 mg 3.7 *** Empagliflozin 25 mg * ** Exenatide 10 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Albiglutide Dulaglutide 0.75 mg Dulaglutide 1.5 mg *p<0.05; **p<0.001; ***p< DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT-2i, sodium-glucose co-transporter-2 inhibitor 1. Lavalle-González FJ et al. Diabetologia 2013;56: ; 2. Roden M et al. Lancet Diabetes Endocrinol 2013;1: ; 3. Bergenstal R et al. Lancet 2010;376: ; 4. Pratley R et al. Int J Clin Pract 2011;65: ; 5. Ahren B et al. Diabetes Care 2014;37: ; 6. Nauck M et al. Diabetes Care 2014;37:

30 Back to our case, in 2017: 52-year-old female Patient characteristics Diabetes history Glucose-lowering therapy HbA 1c 8.1% Weight T2D for 8 years Metformin 1500 mg/day 99.4 kg BMI 34.2 kg/m 2 BMI, body mass index; HbA 1c, glycosylated haemoglobin; T2D, type 2 diabetes

31 Audience Question: How would you intensify treatment in this patient to improve glycemic control? T2D 8 years, HbA 1c 8.1%, weight 99.4 kg, BMI 34.2 kg/m 2 Choose one A.Sulfonylurea B.Insulin analogue C.GLP-1 RA D.DPP-4i E.SGLT-2i BMI, body mass index; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated haemoglobin; SGLT-2i, sodium-glucose co-transporter-2 inhibitor; T2D, type 2 diabetes

32 Paradigm shifts in the last decade Glucose control matters Get to goal safely Treat the whole patient, for the long run

33 Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes (EMPA-REG) CI, confidence interval; HR, hazard ratio Zinman B et al. N Engl J Med 2015 Sept 17

34 Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (LEADER) Compared to placebo, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide. Marso SP et al. N Engl J Med 2016;375:

35 Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (LEADER) Marso SP et al. N Engl J Med 2016;375:

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37 Audience Poll: Did you attend the CANVAS presentation at the ADA in San Diego this last week? A) Yes B) No

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61 Where DO newer therapies fit?

62 Where do newer therapies fit? Williams Textbook of Endocrinology 2016

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65 NIH glycemia reduction approaches in diabetes: A comparative effectiveness study (GRADE) Screening T2D Treated with metformin alone HbA 1c 6.8% at screening <10 <10 years duration at screening Metformin run-in Titrate metformin to 1,000 (min) 2,000 (goal) mg/day HbA 1c % at final run-in visit Randomisation n=5,000 eligible participants Sulfonylurea (glimepiride) n=1,250 DPP-4 inhibitor (sitagliptin) n=1,250 GLP-1 RA (liraglutide) n=1,250 Insulin (glargine) n=1,250 DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated haemoglobin; NIH, National Institutes of Health; T2D, type 2 diabetes Nathan DM et al. Diabetes Care 2013;36:

66 Case #3: Addressing postprandial glucose Ms LD 62-year-old patient with a 12-year history of T2DM She has been on metformin 1 g bid and glimepiride 8 mg daily for the past 5 years Because of an elevated A1c of 8.9%, bedtime glargine was added 1 yr ago. Currently on 46U hs Currently no symptoms of hyper- or hypoglycemia Otherwise well. No clinical history of CVD Meds: Atorvastatin 40 mg daily Irbesartan 300 mg daily On Exam: BMI=31.2 BP=134/ lb (82.7 kg) Abdominal obesity Otherwise Normal

67 Case #3 - Labs Lab: FPG=108 mg/dl A1c=7.9% Renal and liver function normal

68 Results of SMBG Breakfast Lunch Supper HS Before After Before After Before After Monday Tuesday Wednesday Thursday Friday

69 Diabetes Management Case Study Audience Response Question A) <6.5% B) <7.0% C) <7.5% D) <8.0% E) <8.5% What is your target A1c for her:

70 Case #3: Audience Response Question What would be your preferred strategy to bring her A1c to target? A) Change the dose or timing of the glargine B) Add a DPP4 inhibitor C) Add a GLP1 RA D) Add a thiazolidinedione E) Add an SGLT2 inhibitor Breakfast Lunch Supper HS Before After Before After Before After Monday Tuesday Wednesday Thursday Friday

71 LixiLan-L: Patients with T2DM not controlled on basal insulin DESIGN: Randomized, open label, parallel-group, 30-week treatment trial 7% HbA 1c 10% FPG 140 mg/dl iglar dose 50 U iglar ± Metformin n=369 T2DM patients with: Basal insulin >6 months Stable dose U/d Up to 2 OADs iglarlixi ± Metformin HbA 1c 7.5% 10% FPG mg/dl n=367 iglar introduced and/or titrated/ stabilized 6-week run-in phase iglar dose adjusted to SMPG target (80 to 100 mg/dl) and capped to 60 U/day in both groups 30-week treatment period Only metformin was continued. Non-metformin OADs were discontinued after the start of the run-in phase FPG, fasting plasma glucose; HbA 1c, glycated hemoglobin; OADs, oral antidiabetic drugs; SMPG, self-measured plasma glucose; T2DM, type 2 diabetes mellitus Aroda VR et al, Diabetes Care 2016

72 LixiLan-L: Demographic & Baseline Characteristics iglarlixi (n=367) iglar (n=369) All (N=736) Age (years) Female (%) Caucasian/Black (%) 92/5 92/6 92/5 Body weight (kg) at Baseline BMI (kg/m 2 ) at Baseline % Patients with BMI 30 kg/m Diabetes duration (yrs) Duration of basal insulin treatment (yrs) Basal insulin type at Screening (%) iglar Detemir NPH iglar dose (U) at Baseline OAD use at Screening (%) None Metformin Sulfonylurea (SU) DPP-4 inhibitor Metformin + SU Metformin + DPP-4 inhibitor BMI, body mass index; DPP-4, dipeptidyl peptidase 4; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug Aroda VR et al, Diabetes Care 2016

73 Mean ± SE LixiLan-L: Mean HbA 1c Change HbA 1c over time (%) Screening iglarlixi 8.5 iglar Baseline Week LS mean change LS mean difference 95% CI, p-value ( to 0.397) p< % % mitt iglarlixi iglar S BL LOCF Week 77 BL, baseline; CI, confidence interval; HbA 1c, glycated hemoglobin; LS, Least squares; LOCF, Last observation carried forward; mitt, modified intent-to-treat; MMRM, mixed-effect model with repeated measures; S, Screening; SE, standard error Aroda VR et al, Diabetes Care 2016

74 Mean ± SE (mmol/l) LixiLan-L: Mean Plasma Glucose and Glucose Excursion* Mean plasma glucose (mg/dl) LS mean change from baseline iglarlixi iglar Plasma glucose LS mean difference 95% CI, p-value 60.0 ( 70.1 to 50.0) iglarlixi at baseline iglarlixi at Week 30 iglar at baseline iglar at Week 30 Glucose excursion LS mean difference 95% CI, p-value 61.8 ( 70.7 to 52.7) p< Mean ± SE (mg/dl) Pre-injection Pre-meal 30-minute postprandial 1-hour postprandial 2-hour postprandial *Standardized liquid breakfast meal; LS mean difference vs iglar. mitt; ANCOVA CI, confidence interval; LS, least squares; mitt, modified intent-to-treat; SE, standard error

75 Patients (%) LixiLan-L: Patients Reaching Target HbA 1c at Week %* 95% CI: 18.9 to 32.1 p< iglarlixi iglar %* 95% CI: 13.9 to 25.6 p< mitt HbA 1c <7% HbA 1c 6.5% *Weighted average of proportion difference between treatment groups CI, confidence interval; HbA 1c, glycated hemoglobin; mitt, modified intent-to-treat Aroda VR et al, Diabetes Care 2016

76 Audience Poll: How many saw the DUAL VII results at the ADA in San Diego this year? A) Yes B) No 81 June 22, 2017

77 DUAL VII: IDegLira vs Basal Bolus Insulin in Type 2 Diabetes IDegLira Adapted from

78 DUAL VII: IDegLira vs Basal-Bolus Insulin IDegLira IDegLira Adapted from: al/investor_presentations/2017/ %20- %20ADA%202017%20Investor%20presentation.pdf

79 IDegLira IDegLira Adapted from: rmaterial/investor_presentations/2017/ %20- %20ADA%202017%20Investor%20presentation.pdf

80 Included with permission from AACE, for educational purposes only, June 2017

81 Summary Allowing for individualizing of glycemic targets, achieving glucose control minimises long-term risk of complications and remains a forefront of diabetes care Over the past ~decade, a myriad of treatments have emerged to address efficacy while minimising weight gain and hypoglycemia GLP-1 RA and SGLT2 inhibitors demonstrate high glycemic efficacy DPP-4 inhibitors are well tolerated Treatment paradigms in diabetes are shifting toward longerterm comprehensive goals, including durability, safety and cardiovascular risk.

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83 EXTRA SLIDES 88 June 22, 2017