Novo Nordisk 10 Year Ambition for

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1 Novo Nordisk 10 Year Ambition for Obesity disease: pathophysiology, Obesity consequences and management beyond weight loss significantly opened up the market by specifically addressing barriers across stakeholders Obesity will be widely recognised as a chronic disease Within 10 years Novo Nordisk will have a loss efficacy R. Medlej, 2018% weight

2 GLP-1 is a physiological regulator of appetite and energy intake Obesity is a chronic disease requiring long-term management GLP-1 is a physiological regulator of appetite and energy intake Liraglutide, a once-daily human GLP-1 analogue, reduces appetite and energy intake Efficacy and safety of liraglutide 3.0 mg in weight management GLP-1, glucagon-like peptide-1

3 Definition of obesity Obesity is defined as abnormal or excessive fat accumulation that may impair health Body mass index (BMI) provides the most convenient populationlevel measure of overweight and obesity currently available weight (kg) BMI = height (m 2 ) Classification BMI (kg/m 2 ) Underweight <18.5 Normal range 18.5 and <25 Overweight 25 and <30 Obesity 30 Obesity class I 30 and <35 Obesity class II 35 and <40 Obesity class III 40 WHO. Factsheet

4 Control of Energy Metabolism COGNITIVE REPONSE Afferent Signals Neural Hormones Nutrients CENTRAL CONTROL HYPOTHALAMUS Neurotransmitters Neuropeptides Efferent Signals Autonomic nervous system Adipose tissue Pancreas Gut Peripheral Organs

5 MOLECULES IMPLICATED IN ENEGY METABOLISM Appetite NPY Agouti-related protein Ghréline Noradrénaline (α 2) Opioïdes Endocanabinoides (CB1-R) Appetite - Leptine - POMC,α MSH (MC4-R) Serotonin Dopamine CCK GLP-1 PYY 3-36 Insulin Glucose, FFA..

6 Obesity is a complex and multifactorial disease with multiple pathophysiologic origins Environmental Epigenetic Genetic 40-70% Obesity Sociocultural Physiologic Behavioral Bray GA, et al. Lancet. 2016;387:

7 Obesity is a complex and multifactorial disease Energy intake Energy expenditure Mesolymbic (reward)system Dopamine, Serotonine, Endocanabinoides Hedonic input Experienced palatability or pleasure Environment Inactive lifestyle, smoking cessation, psychosocial factors Genetics Medications 1. Badman, Flier. Science 2005;307: ; 2. US Department of Health and Human Services, NIH Publication No

8 Age-standardized prevalence of obesity: Men Women In Lebanon,The prevalence of obesity is 31%2 Prevalence of Obesity < Values for prevalence are provided as decimals 1.GBD 2015 Obesity Collaborators N Engl J Med 2017 Jun 12 [Epub ahead of print] 2. The World Factbook, retrieved from on July 24, >0.35

9 Obesity is recognised as a disease and health issue WOF The World Obesity Federation takes the position that obesity is a chronic, relapsing, progressive disease process and emphasizes the need for immediate action for prevention and control of this global epidemic 1 CON Obesity is characterized by excess body fat that can threaten or affect your health. Many organizations including the Canadian Obesity Network, now consider obesity to be a chronic disease. 4 AMA World Obesity Federation American Medical Association recognizes obesity and overweight as a chronic medical condition (de facto disease state) and urgent public health problem and work towards the recognition of obesity intervention as an essential medical service 2 American Medical Association EASO Canadian Obesity Network A progressive disease, impacting severely on individuals and society alike, it is widely acknowledged that obesity is the gateway to many other disease areas 5 European Association for the Study of Obesity FDA Obesity is a chronic relapsing health risk defined by excess body fat 3 The US Food and Drug Administration EMA Obesity is recognised as a chronic clinical condition and is considered to be the result of interactions of genetic, metabolic, environmental and behavioural factors, and is associated with increases in both morbidity and mortality 6 European Medicines Agency Bray et al. Obes Rev 2017;18:715 23; 2. AMA resolutions. June Available here; 3. Food and Drug Administration. Guidance for Industry Developing Products for Weight Management 2007 Available here; 4. Canadian Obesity Network. Available here; 5. EASO: 2015 Milan Declaration: A Call to Action on Obesity. Available here; 6. EMA Draft Guideline on clinical evaluation of medicinal products used in weight control EMA/CHMP/311805/2014. Available here.

10 Life expectancy decreases as BMI increases Proportion still alive (%) BMI range (kg/m 2 ) Normal BMI = almost 80% chance of reaching age 70 BMI = ~60% chance of reaching age 70 BMI = ~50% chance of reaching age 70 Age (years)

11 Obesity is associated with multiple comorbidities Metabolic, Mechanical and Mental Metabolic Mechanical Mental Mental health Depression Anxiety Asthma Fatty liver 3 Sleep Apnoea Cardiovascular diseases Stroke Dyslipidaemia Hypertension Coronary artery disease Coronary heart failure Pulmonary embolism Cancers* Physical functioning Gallstones Infertility Incontinence Arthrosis Chronic back pain Type 2 diabetes Prediabetes Thrombosis Gout *Including breast, colorectal, endometrial, esophageal, kidney, ovarian, pancreatic and prostate Adapted from Sharma AM. Obes Rev. 2010;11:808-9; Guh et al. BMC Public Health 2009;9:88; Luppino et al. Arch Gen Psychiatry 2010;67:220 9; Simon et al. Arch Gen Psychiatry 2006;63:824 30; Church et al. Gastroenterology 2006;130: ; Li et al. Prev Med 2010;51:18 23; Hosler. Prev Chronic Dis 2009;6:A48

12 Insulin Resistance AngioTNG Leptin Adiponectin TNF α FFA Stroke

13 Cancer It is estimated that obesity accounts for ~ 20% of all cancer cases. In a large review obesity was the cause of a quarter to onethird of cancers of the colon, breast, endometrium, kidney and oesophagus. It is also associated with increased risk of gastric, pancreatic, gallbladder cancer, as well as leukaemia. Furthermore, prognosis is poorer in obese individuals who develop some cancer types. Weight loss has been shown to reduce the risk of some cancers including breast cancer, particularly among postmenopausal women.

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15 NAFLD & NASH Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of chronic liver disease worldwide, estimated to be present in 20 35% of adults in the developed world. One-third of these cases progress to non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis and hepatocellular carcinoma. Risk of NAFLD is strongly correlated with BMI. (steatosis found in 15% in non-obese persons, 65% in people with Class I or II obesity and 85% in Class III obesity). Weight loss is the best treatment for NAFLD with studies showing bariatric surgery-induced weight loss leading to resolution of NASH in 80% of cases.

16 Weight loss leads to improvement of many obesity related comorbidities Benefits of 5 10% weight loss Reduction in risk of type 2 diabetes 1 Reduction in CV mortality 2 Improvements in blood lipid profile 3 Improvements in blood pressure 4 Improvements in severity of obstructive sleep apnoea 5,6 Improvements in health-related quality of life 7,8 1. Knowler et al. N Engl J Med 2002;346: ; 2. Li et al. Lancet Diabetes Endocrinol 2014;2:474 80; 3. Datillo et al. Am J Clin Nutr 1992;56:320 8; 4. Wing et al. Diabetes Care 2011;34:1481 6; 5. Foster et al. Arch Intern Med 2009;169: ; 6. Kuna et al. Sleep 2013;36:641 9; 7. Warkentin et al. Obes Rev 2014;15:169 82; 8. Wright et al. J Health Psychol 2013;18:574 86

17 Maintenance of weight loss is challenging 5 Anderson et al. Foster et al. Graham et al. Hensrud et al. Jordan et al. Kramer et al. Lantz et al. Murphy et al. Pekkarinen & Mustajoki Stalonas et al. Stunkard & Penik Wadden & Frey Wadden et al. Walsh & Flynn Weight change (kg) Mean change from baseline to end of diet (kg) Mean change from baseline to follow-up (kg) Follow up range from 4 to 7 years Mann et al. Am Psychol 2007;62:220 33

18 Physiological responses to weight loss favour weight regain 1 2 Energy intake Resting energy expenditure Hunger Desire to eat Leptin Adipose tissue Insulin GLP-1, CCK, PYY, Ghrelin Pancreas Gut CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; PYY, peptide YY 1. Schwartz et al. Obes Rev 2010;11:531 47; 2. Sumithran et al. N Engl J Med 2011;365:

19 Pharmacotherapy in addition to diet and exercise can help patients achieve clinically relevant weight loss Pharmacotherapy alone Lifestyle modification alone Weight change (kg) Pharmacotherapy + brief lifestyle modification Combined therapy Weeks Data are mean ± SE Pharmacotherapy: sibutramine; Pharmacotherapy alone: Patients received a daily dose of 15 mg/day; Lifestyle modification alone: Patients attended 30 lifestyle counselling sessions; Pharmacotherapy + brief therapy: Patients were given sibutramine and received brief lifestyle counselling; Combined therapy: Patients received sibutramine and attended 30 lifestyle counselling sessions. Wadden et al. N Engl J Med 2005;353:

20 Unmet pharmacological need for obesity treatment Lifestyle modification 1 Pharmacotherapy plus lifestyle modification 1 Gastric band 2 Gastric sleeve 2 Gastric bypass Weight loss (%) 1. Jensen et al. Circulation 2014;129(25 Suppl 2):S102 38; 3. Courcoulas et al. JAMA 2013;310: ; 3. Obesity Drug Outcome Measures: A Consensus Report of Considerations Regarding Pharmacologic Intervention. Available at: (accessed 15 February 2016)

21 Clinical management of obesity AHA/ACC/TOS guidelines Guidance centred around weight loss as means of CV risk Diet and exercise remain cornerstone of weight loss interventions Participation in a long-term ( 1 year) comprehensive weight loss maintenance programme is strongly recommended Surgery may be appropriate after diet and exercise and pharmacotherapy failure AHA, American Heart Association; ACC, American College of Cardiology; CV, cardiovascular; TOS, The Obesity Society Jensen et al. J Am Coll Cardiol 2014;63(25 Pt B):

22 GLP-1 is a physiological regulator of appetite and energy intake Obesity is a chronic disease requiring long-term management GLP-1 is a physiological regulator of appetite and energy intake Liraglutide, a once-daily human GLP-1 analogue, reduces appetite and energy intake Efficacy and safety of liraglutide 3.0 mg in weight management GLP-1, glucagon-like peptide-1

23 GLP-1 is released in response to food intake 50 Meal Meal Meal GLP-1 n=6 Plasma GLP-1 concentration (pmol/l) Time (h) 24 Adapted from: Orskov et al. Scand J Gastroenterol 1996;31:665 70

24 Metabolic effects of GLP-1 Appetite 1 Satiety Fullness Hunger Prospective food consumption Energy intake Glucose regulation 2 (Glucose-dependent) Insulin secretion Glucagon secretion Gastric effects 3,4 Gastric acid Gastric emptying GLP-1, glucagon-like peptide-1 1. Flint et al. J Clin Invest 1998;101:515 20; 2. Nauck et al. Diabetologia 1993;36:741 4; 3. O'Halloran et al. J Endocrinol 1990;126:169 73; 4. Nauck et al. Am J Physiol 1997;273:E981 8

25 Liraglutide, a once-daily human GLP-1 analogue, reduces appetite and energy intake Obesity is a chronic disease requiring long-term management GLP-1 is a physiological regulator of appetite and energy intake Liraglutide, a once-daily human GLP-1 analogue, reduces appetite and energy intake Efficacy and safety of liraglutide 3.0 mg in weight management GLP-1, glucagon-like peptide-1

26 Liraglutide is a once-daily, human GLP-1 analogue His Ala Glu Gly Thr Phe Thr Ser Asp Val Human endogenous GLP-1 Lys Glu Ala Ala Gln Gly Glu Leu Tyr Ser Ser Phe Ile Ala Trp Leu Val Lys Gly Arg Gly C-16 fatty acid (palmitoyl) T ½ = ~2 mins His Ala Glu Gly Thr Phe Thr Ser Glu Lys Glu Ala Ala Gln Gly Glu Phe Ile Ala Trp Leu Val Arg Leu Tyr Gly Arg Asp Val Ser Ser Gly Liraglutide 97% amino acid homology to human GLP-1; improved PK: albumin binding through acylation; heptamer formation Slow absorption from subcutis Resistant to DPP-4 Long plasma half-life (T ½ =13 h) DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PK, pharmacokinetics; T ½, plasma half-life Knudsen et al. J Med Chem 2000;43:1664 9; Degn et al. Diabetes 2004;53:

27 Liraglutide 3.0 mg influences all dimensions of appetite Satiety (mm) 100 Satiety Fullness (mm) 100 Fullness Liraglutide 3.0 mg 80 Placebo Hunger (mm) 100 Hunger Time (min) Time (min) Appetite ratings were assessed by visual analog scale. Data are presented as mean ± standard error. PFC, prospective food consumption Adapted from: van Can et al. Int J Obes 2014;38: PFC (mm) 100 Prospective food consumption

28 Efficacy and safety of liraglutide 3.0 mg in weight management Obesity is a chronic disease requiring long-term management GLP-1 is a physiological regulator of appetite and energy intake Liraglutide, a once-daily human GLP-1 analogue, reduces appetite and energy intake Efficacy and safety of liraglutide 3.0 mg in weight management GLP-1, glucagon-like peptide-1

29 SCALE Phase 3a clinical trial programme Liraglutide 1.8 mg is not approved for weight management SCALE Obesity and Prediabetes (1839) 1 SCALE Maintenance (1923) 3 Weight management & delayed onset of diabetes Liraglutide 3.0 mg n=2487 Placebo n=1244 Prevention of weight regain Liraglutide 3.0 mg n=212 Placebo n=210 SCALE Diabetes (1922) 2 SCALE Sleep Apnoea (3970) 4 Weight management in type 2 diabetes Liraglutide 3.0 mg n=423 Liraglutide 1.8 mg n=211 Placebo n=212 Effect of liraglutide in subjects with obesity and moderate to severe OSA Liraglutide 3.0 mg n=180 Placebo n=179 *SCALE, Sleep apnoea 3970 trial BMI 30 kg/m 2 plus co-morbidities; BMI, body mass index; OSA, obstructive sleep apnoea; SCALE, Satiety and Clinical Adiposity Liraglutide Evidence in individuals with and without diabetes 1. Pi-Sunyer et al. N Engl J Med 2015;373:11 22; 2. Davies et al. JAMA 2015;314:687 99; 3. Wadden et al. Int J Obes (Lond) 2013;37: ; 4. Blackman et al. Int J Obes (Lond). 2016;40:1310-9

30 Trial design: SCALE Obesity and Prediabetes Liraglutide 3.0 mg in weight management (56 weeks) 3731 participants 18 years Stable BW BMI 30 kg/m 2 or 27 kg/m 2 + comorbidities Without prediabetes With prediabetes 1 Liraglutide 3.0 mg (n=959) Placebo (n=487) Liraglutide 3.0 mg (n=1528) Placebo (n=757) Lifestyle intervention: -500 kcal/day diet min/week physical activity Dose escalation 0 4 weeks Treatment duration 52 weeks 12 weeks 2-week FU Trial information June 2011 to March 2013 Randomised controlled double-blind study 191 sites in 27 countries Duration: 56 weeks (with prediabetes), 68 weeks (without prediabetes) Randomisation (2:1) Re-randomisation (1:1) EOT Trial objective Efficacy and safety of liraglutide 3.0 mg, as adjunct to D&E, in participants with obesity or overweight plus comorbidities, without diabetes Key endpoints Three co-primary: BW change, 5% or 10% BW loss Secondary: Changes from baseline in BMI, WC, glycaemic control variables, cardiometabolic risk factors, and HRQoL 1. ADA. Diabetes Care 2010;33(Suppl. 1):S11 61 BW, body weight; D&E, diet and exercise; EOT, end of treatment; FU, follow-up; HRQoL, health-related quality of life; WC, waist circumference Pi-Sunyer et al. N Engl J Med 2015;373:11 22

31 Change in body weight (%) 0 56 weeks Mean baseline weight: 106 kg 0 Liraglutide 3.0 mg Observed mean LOCF Placebo Observed mean LOCF Change in weight (%) % -3.5% -8.0% -9.2% p< Week FAS, fasting visit data only. Line graphs are observed means (±SE). Statistical analysis is ANCOVA. FAS, full analysis set; LOCF, last observation carried forward; SE, standard error Pi-Sunyer et al. Diabetologia 2014;57(Suppl. 1): Abstract 73-OR

32 Liraglutide 3mg locally approved insert leaflet version STF Dec 2017

33 Individuals with prediabetes at week 56 In individuals with normoglycaemia at screening Individuals with prediabetes (%) Liraglutide 3.0 mg p< Placebo 20.7 At screening 56 weeks FAS LOCF. Graphs are observed proportions. Statistical analysis is logistic regression. In this analysis prediabetes includes subjects with transient and confirmed type 2 diabetes. EOR, estimated odds ratio; FAS, full analysis set; LOCF, last observation carried forward Adapted from Pi-Sunyer et al. N Engl J Med 2015;373:11 22

34 Individuals with prediabetes at week 56 In individuals with prediabetes at screening Individuals with prediabetes (%) Liraglutide 3.0 mg p< Placebo 67.3 At screening 56 weeks FAS LOCF. Graphs are observed proportions. Statistical analysis is logistic regression. In this analysis prediabetes includes subjects with transient and confirmed type 2 diabetes. EOR, estimated odds ratio; FAS, full analysis set; LOCF, last observation carried forward Adapted from Pi-Sunyer et al. N Engl J Med 2015;373:11 22

35 Changes in blood pressure and pulse 0 56 weeks Mean baseline SBP: 123 mmhg Mean baseline DBP: 79 mmhg Mean baseline pulse: 71 bpm Change in SBP (mmhg) Change in DBP (mmhg) Change in pulse (bpm) Liraglutide 3.0 mg Observed mean LOCF Placebo Observed mean LOCF Week * * 2.5* 0.1 FAS, LOCF (blood pressure); SAS, LOCF (pulse). Data are observed means (±SE) of all participants attending each visit. Statistical analyses are ANCOVA. *p< ANCOVA, analysis of covariance; bpm, beats per minute; DBP, diastolic blood pressure; FAS, full analysis set; LOCF, last observation carried forward; SAS, safety analysis set; SBP, systolic blood pressure; SE, standard error Pi-Sunyer et al. N Engl J Med 2015;373:11 22

36 Change in fasting lipids 0 56 weeks Liraglutide 3.0 mg Placebo Change from baseline (%) ETD -2.3 (-3.3, -1.3) P< Total cholesterol ETD -2.4 (-4.0, -0.9) P=0.002 LDL cholesterol ETD 1.9 (0.7, 3.0) P=0.001 HDL cholesterol ETD -9.1 (-11.4, -6.8) P< VLDL cholesterol ETD -3.9 (-5.2, -2.5) P< Non-HDL cholesterol ETD -9.3 (-11.5, -7.0) P< Triglycerides ETD -4.2 (-7.3, -0.9) P=0.01 Free fatty acids FAS, LOCF. Data are based on observed geometric means. Statistical analysis is ANCOVA. ETD, estimated treatment difference (95% CI); FAS, full analysis set; LOCF, last observation carried forward Pi-Sunyer et al. N Engl J Med 2015;373:11 22

37 Change in cardiovascular biomarkers 0 56 weeks Liraglutide 3.0 mg Placebo Change from baseline (%) ETD (-34.3, -26.5) P< ETD 8.5 (5.5, 11.6) P<0.001 ETD 0.5 (-1.2, 2.1) P= ETD -3.6 (-10.1, 3.4) P=0.31 hscrp Adiponectin Fibrinogen Urinary albumin: creatinine ratio 14.9 FAS, LOCF. Data are based on observed geometric means. Statistical analysis is ANCOVA. Data for PAI-1 not available. Data are shown as % change from baseline. Units of measure were hscrp (mg/l); Adiponectin (mg/l); Fibrinogen (g/l); Urinary albumin: creatinine ratio (mg/mol). FAS, full analysis set; ETD, estimated treatment difference (95% CI); LOCF, last observation carried forward Pi-Sunyer et al. N Engl J Med 2015;373:11 22

38 Summary of IWQOL-Lite 0 56 weeks Increase = Improvement Liraglutide 3.0 mg Placebo 15 * * Mean change (score) 10 5 * * * * 0 Total Score Physical Function Self- Esteem Sexual Life Public Distress Work FAS LOCF. Bar graph is observed mean change from baseline. Statistical analysis is ANCOVA. *p<0.01 FAS, full analysis set; IWQOL-Lite, Impact of weight on quality of life-lite questionnaire; LOCF, last observation carried forward Pi-Sunyer et al. N Engl J Med 2015;373:11 22

39 Proportion of individuals with nausea 0 56 weeks Individuals (%) Liraglutide 3.0 mg Placebo Proportion of patients reporting nausea at: Week 4: 24.7% (liraglutide) vs. 5.4% (placebo) Week 8: 14.7% (liraglutide) vs. 3.2% (placebo) Week 56: 5.5% (liraglutide) vs. 1.7% (placebo) Week Safety analysis set Pi-Sunyer et al. N Engl J Med 2015;373:11 22

40 Weight loss with and without nausea/vomiting 0 56 weeks N 0 With nausea/vomiting Without nausea/vomiting Liraglutide 3.0 mg Placebo Weight change (%) ETD -5.4% ETD -5.5% p=0.81 for interaction between nausea/vomiting and treatment effect Least square means (± standard error); LOCF at end-of-treatment (56 weeks); ETD, estimated treatment difference; LOCF, last observation carried forward; N, number of subjects contributing to analysis Lean et al. AACE 2015; Poster 611. Abstract available here.

41 SCALE Obesity and Prediabetes (56 weeks) Summary Liraglutide 3.0 mg once-daily, as an adjunct to diet and exercise, was associated with clinically meaningful weight loss in individuals with obesity or with overweight and comorbidities Liraglutide 3.0 mg was also associated with improvements in glycaemia, cardiometabolic risk factors and health-related quality of life Safety profile was generally consistent with that of previous clinical trials with liraglutide 3.0 mg and liraglutide 1.8 mg in individuals with T2D Liraglutide 3.0 mg was generally well tolerated with nausea, diarrhoea and constipation being the most commonly reported adverse events CV, cardiovascular; HRQoL, health-related quality of life; T2D, type 2 diabetes Pi-Sunyer et al. New Engl J Med 2015;373:11 22

42 Trial design: SCALE Obesity and Prediabetes extension Liraglutide 3.0 mg in weight management (160 weeks) Inclusion criteria: 18 years Stable BW BMI 30 kg/m 2 or 27 kg/m 2 + comorbidities Without prediabetes With prediabetes 1 Liraglutide 3.0 mg Placebo Liraglutide 3.0 mg (n=1505) Placebo (n=749) Trial information June 2011 to March 2015 Randomised controlled double-blind study 191 sites in 27 countries Lifestyle intervention: -500 kcal/day diet min/week physical activity Dose escalation 0 4 weeks Treatment duration 156 weeks 12-week off-drug FU Randomisation (2:1) Trial objective Efficacy of liraglutide 3.0 mg (after 160 weeks of treatment) in delaying the onset of T2DM in participants with obesity or overweight with comorbidities, and diagnosed with prediabetes at screening 160 weeks End of trial Key endpoints Primary: time to onset of T2DM at 160 weeks Secondary: weight measures, glycaemic control variables, cardiometabolic risk factors, HRQoL, safety and tolerability 1. ADA. Diabetes Care 2010;33(Suppl. 1):S62 9 BW, body weight; D&E, diet and exercise; FU, follow-up; HRQoL, health-related quality of life; T2DM, type 2 diabetes mellitus le Roux et al. Lancet 2017;389:

43 Participants diagnosed with T2DM over time Kaplan Meier plot: weeks 12 Liraglutide 3.0 mg Off drug follow up Placebo Off drug follow up Placebo: 11% Liraglutide 3.0 mg: 3% Participants (%) n= n= Week Full analysis set. Numbers in the figure correspond to the accumulated number of diagnosed participants T2DM, type 2 diabetes mellitus le Roux et al. Lancet 2017;389:

44 Change in body weight (%) weeks Change in weight (%) n= n= Liraglutide 3.0 mg Off-drug follow-up Observed mean LOCF -3.5% -9.2% Placebo Off-drug follow-up Observed mean LOCF Week -3.4% -8.5% -1.9% -6.1% ETD at week 160: 4.3% [ 4.9; 3.7] p< % -7.1% % -5.2% Full analysis set, fasting visit data only. Line graphs are observed means (±SE) LOCF, last observation carried forward; SE, standard error le Roux et al. Lancet 2017;389:

45 Change in SBP (mmhg) weeks Change in SBP (mmhg) n= n= Liraglutide 3.0 mg Off drug follow up Observed mean LOCF Week Placebo Off drug follow up Observed mean LOCF ETD at week 160: -2.8 [-3.8;-1.8] p< Full analysis set. Line graphs are observed means (±SE) LOCF, last observation carried forward; SBP, systolic blood pressure; SE, standard error le Roux et al. Lancet 2017;389:

46 Summary of IWQoL-Lite Mean change from baseline at 160 weeks Liraglutide 3.0 mg Placebo Increase = Improvement 20 Score mean change * * * * * * 0 Physical function Selfesteem Sexual life Public distress Work Total score Minimal important difference: for total score 1 Full analysis set, last observation carried forward. Bar graph is observed means. Statistical analysis is ANCOVA. *p< Crosby et al. J Clin Epidemiol 2004;57: ANCOVA, analysis of covariance; IWQoL-Lite, Impact of weight on quality of life-lite questionnaire le Roux et al. Lancet 2017;389:

47 Conclusions Three years of treatment with once-daily subcutaneous liraglutide 3.0 mg, as an adjunct to a life style modification, reduced the risk of T2DM in individuals with overweight or obesity and prediabetes, and promoted greater weight loss and improvements in glycaemic control and cardiometabolic risk factors compared with placebo Liraglutide 3.0 mg, as a GLP-1RA, has also direct glucose-dependent effects on insulin secretion in addition to weight-loss mediated reduction in insulin resistance Liraglutide 3.0 mg is generally well tolerated. GLP-1RA, glucagon-like peptide-1 receptor agonist; T2DM, type 2 diabetes mellitus le Roux et al. Lancet 2017;389:

48 Liraglutide 1.8 mg is not approved for weight management Label update!! Liraglutide 3mg is the only anti-obesity treatment to include CV benefit data (significant decrease in CV death) in its label (LEADER study) From liraglutide 1.8 mg T2D trial data to liraglutide 3.0 mg for weight management Overlapping body weights Overlapping exposure T2D trials (doses up to 1.8 mg) Weight management trials (doses up to 3.0 mg) Proportion Proportion Red line = maximum exposure in T2D The LEADER trial, characterizes the CV risk of liraglutide, (1.8 mg) dose Body weight (kg) AUC (mg.h/l) AUC, area under the curve Novo Nordisk Briefing Document: Liraglutide 3.0 mg for weight management NDA Click Here.

49 Liraglutide dosing and titration 1. Liraglutide locally approved insert leaflet version STF Dec 2017

50 Summary Obesity is a chronic challenging disease with multiple comorbidities. 5-10% weight loss significantly improves most comorbidities (risk of T2D, CV mortality, blood lipids, BP, OSA, NAFLD and quality of life) Liraglutide 3mg safely provides significant weight loss and helps maintain weight loss on the long term: Assessment should be done after 12 weeks on the 3 mg dose (16 weeks of treatment if the titration phase takes 4 weeks) to decide if the patient is a responder (weight loss 5%) or not (less than 5% weight loss) Responders are predicted to reach a weight loss of 11.2% at 56 weeks Liraglutide 3mg provides benefits beyond weight loss: On glucose control with a 69% regression to normoglycemia in patients with prediabetes, and 80% risk reduction of developing type 2 diabetes. Is the only anti-obesity treatment to include CV benefit data

51 THE END THANK YOU