2016 년대한당뇨병학회춘계학술대회 The New Trend of Anti-Obesity Drug MIN-SEON KIM ASAN MEDICAL CENTER
Conflict of Interest Nothing to declare
Index Introduction: Obesity Epidemiology, Pathophysiology and Comorbidity Endocrine society clinical practice guideline History of anti-obesity drugs Anti-obesity drugs currently approved by FDA Lorcaserin (BELVIQ) Phentermine/topiramate (Qsymia) Naltrexone/bupropion (Contrave) Liraglutide (Saxenda)
Trends in prevalence of BMI categories (Men) (Women) Men Women NCD Risk Factor Collaboration, Lancet, 2016
Prevalence of obesity (Korea) 40 35 30 25 20 15 Total Male Female 10 5 0 1995 1998 2001 2005 2007 2008 2009 2010 2011 2012
Prevalence of obesity in DM patients (KDA fact sheet)
Physiological Impact of Obesity
Obesity T2DM 당뇨병발병위험 : 비만남성은 7 배, 비만여성은 12 배높다. Guh DP, BMC public health, 2009, 9:88
Obesity insulin resistance Free fatty acid Adipokine Leptin Adiponectin Resistin TNF- IL-6 PAI-1 Fatty liver Gluconeogenesis Glucose utilization Insulin secretion vascular dilatation
Obesity inflammation insulin resistance!
Obesity inflammation CVD
Weight reduction and health benefits Pharmacological management of obesity, J Clin Endocrinol Metab, 2015
Endocrine Society Clinical Practice Guideline Recommendation Diet, exercise, and behavioral modification : BMI 25 kg/m2 Pharmacotherapy and behavioral modification : BMI 30 kg/m2 or BMI 27 kg/m2 with comorbidity (HTN, dyslipidemia, T2DM and OSA) Bariatric surgery with behavioral modification : BMI 40 kg/m2 or BMI 35 kg/m2 with comorbidity (HTN, dyslipidemia, T2DM and OSA) Assessment of efficacy and safety of weight loss medication : at least monthly for the first 3 months at least every 3 months If deemed effective (weigt loss 5 % of body weight at 3 mo), continue If deemed ineffective (weight loss <5% at 3 mo), discontinue or consider alternative treatment
Lorcaserin (BELVIQ)
Mechanism of Lorcaserin
J Pharmacol Exp Ther. 2008 May;325(2):577-87. Development of Lorcaserin 5-HT agonist weight loss 5-HT 2C Selective 5-HT2C agonist AE 5HT2B agonist CV Disease (Sibutramine) 5-TH 2A agonist Hallucinate Lorcaserin hydrochloride ( BELVIQ ) is a selective Serotonin 2C receptor agonist
Clinical trials BLOOM : Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight Management.(N Engl J Med 2010 ; 363(3) : 245-256) BLOSSOM : A One-year Randomized Trial of Lorcaserin for Weight Loss in Obese and Overweight Adults : The BLOSSOM Trial (J Clin Endocrinol Metab 2011 ; 96(10) : 3067-3077) BLOOM-DM : Randomized Placebo-Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 Diabetes Mellitus: The BLOOM-DM Study. (Obesity 2012 ; 20 : 1426-1436) Title Enrolled Duration overweight adults with type 2 DM BLOOM 3,182 2 year Excluded BLOSSOM 4,008 1 year Excluded BLOOM-DM 604 1 year Included
BLOOM Double blind, RCT 3182 명을대상으로한대규모임상시험. BELVIQ 의 2 년안전성및효과입증.
BLOOM - protocol Duration 2 years (year 1 weight loss, year2 maintenance of weight loss) Patients Age of 18 to 65 years, total 3,182patients. BMI of 30 to 45 or of 27 to 45 with at least 1 coexisting condition (hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea). Instruction Return to the research site 2 and 4 weeks. Exercise moderately for 30 minutes daily and to reduce the daily calorie intake to 600 kcal N Engl J Med 2010 ; 363(3) : 245-256
BLOOM protocol Dose < year 1> BELVIQ 10mg BID (n=1595) < year 2> BELVIQ 10mg BID (n=573) Placebo (n=283) Placebo (n=1587) Placebo (n=697) N Engl J Med 2010 ; 363(3) : 245-256
BLOOM weight change year1 BELVIQ Placebo Lost of 5% of body weight Patients (%) *** 66.4% Lost of 10% of body weight Patients (%) *** p<0.001 *** 36.2% *** p<0.001 32.1% 13.6% N Engl J Med 2010 ; 363(3) : 245-256
BLOOM weight change year1 BELVIQ Placebo Weight change (%) -3.3 *** p<0.001 (ITT) -8.1 *** N Engl J Med 2010 ; 363(3) : 245-256
BLOOM weight change year1,2 BELVIQ Placebo Weight change (kg) 감량체중유지환자 (%) *** *** p<0.001 67.9% 50.3% BELVIQ BELVIQ BELVIQ Placebo N Engl J Med 2010 ; 363(3) : 245-256
BLOOM secondary endpoint Placebo BELVIQ p value Fasting glucose (mg / dl) 1.1-0.83 < 0.001 Blood Pressure (mm Hg) Systolic - 0.8-1.4 0.04 Diastolic - 0.6-1.1 0.01 Heart rate (beats per min) -1.6-2.0 0.0499 N Engl J Med 2010 ; 363(3) : 245-256
BLOOM safety year1,2 B = BELVIQ // P = Placebo Year 1 Year 2 B P B B B P P P Headache 18.0 11.0 7.2 6.4 4.3 Upper respiratory infection 14.8 11.9 14.5 11.0 16.1 Dizziness 8.2 3.8 1.7 2.8 2.4 Nausea 7.5 5.4 3.5 3.2 4.2 Dry mouth 5.2 2.3 0.1 1.1 0.3 Constipation 6.7 4.0 2.4 2.8 1.6 N Engl J Med 2010 ; 363(3) : 245-256
BLOOM safety year1,2 Incidence of Valvulopathy at Week 104 N Engl J Med 2010 ; 363(3) : 245-256
BLOOM-DM Behavioral Modification and Lorcaserin for Overweight and Obesity Management Diabetes Mellitus Double blind, RCT 604 명의비만인제 2 형당뇨환자를 대상으로함. 비만한당뇨환자에게 BELVIQ 의투약은체중조절및혈당조절 에도도움을준다는것이입증된시험. Obesity 2012 ; 20 : 1426-1436
BLOOM-DM Duration Patients 1 year Age of 18 to 65 years, total 604 patients. Patients were treated with metformin, a sulfonylurea (SFU) or both; had glycated hemoglobin (HbA1c) 7 10%; had BMI 27 45 Instruction Return to the research site 2 and 4 weeks. Exercise moderately for 30 minutes daily and to reduce the daily calorie intake to 600 kcal Dose 10mg BELVIQ BID n=256 // 10mg BELVIQ QD n=95 // Placebo n=253 Obesity 2012 ; 20 : 1426-1436
BLOOM-DM weight change BELVIQ bid BELVIQ qd Placebo Lost of 5% of body weight Patients (%) *** *** 44.6% 54.7% *** p<0.001 17.9% Lost of 10% of body weight Patients (%) *** 20.8% *** 22.7% *** p<0.001 5.8% Obesity 2012 ; 20 : 1426-1436
BLOOM-DM weight change Weight change (%) - 1.5% - 1.7% - 4.5% *** - 5.5% *** - 5.5% *** - 5.8% *** *** p<0.001 *** p<0.001 Obesity 2012 ; 20 : 1426-1436
BLOOM-DM secondary endpoint Placebo BELVIQ QD p value BELVIQ BID p value Glycemic parameters Fasting glucose (mg/dl) HbA1c (%) -11.9-28.4 P<0.001-27.4 P<0.001-0.4-1.0 P<0.001-0.9 P<0.001 Obesity 2012 ; 20 : 1426-1436
BLOOM-DM safety Obesity 2012 ; 20 : 1426-1436
Phentermine/topiramate (Qsymia)
Phentermine (PHEN) 아드레날린성식욕억제제 Phentermine 은시상하부에서에피네프린분비를촉진하고, 식사섭취량을감소시켜체중감소를촉진함. Serotonine 효과는없음. 1959 년 FDA 는단독요법으로일일 37.5 mg 이하용량으로단기간사용한다는조건으로 phentermine 의비만치료적응증을인정함.
Topiramate (TPM) Topiramate 단독요법은 1996 년간질발작치료적응승인, 2004 년편두통예방승인. 그러나체중관리목적만을위한단독요법은아직허가받지못함. Topiramate 의체중감소기전은명확하지않음. 안전성문제 : 용량이증가할수록인지장애, 이상감각등중추신경계및말초신경계에다양한부작용유발. Topiramate 에 phentermine 을복합처방함으로써, topiramate 의용량을줄여부작용을낮추고, 항비만효과를강화시킨복합제형이개발됨. PHEN/TPM CR 는 2012 년 7 월 FDA 승인.
CONQUER Lancet 2011; 377: 1341 52 대규모 3 상임상연구 CONQUER 연구는미국 93 개연구센터, 전연령대 (18-70 세 ) 2487 명대상 가장많은수의대상환자, SEQUEL 연구로연장 BMI 27-45 kg/m 2, 2 개이상의대상성동반질환 ( 고혈압, 고지혈증, 당뇨병및당뇨병전단계, 복부비만 ) 을가진환자 위약군 : 일일 1 회 PHEN 7.5 mg/ TPM 46.0 mg : PHEN 15 mg/ TPM 92.0 mg = 2:1:2 비율무작위배정
Effect of PHEN/TPM on body weight
Adverse events in the safety population
SEQUEL 2012 Feb;95(2):297-308 SEQUER 연구는항비만약제의장기복용효과를보고자, CONQUER 연구를연장하여총 108 주간의약물효과를조사 676 명의대상환자중이기간을마친환자는 84% 라는높은수치 3 개군에서큰차이가없었음
Mean (95% CI) percentage weight loss from baseline to week 108
Effects of PHEN/TPM CR on metabolic variables
All adverse events with frequency of 5% in any PHEN/TPM CR group
Naltrexone/bupropion (Contrave)
Naltrexone/bupropion Naltrexone 은중추신경계존재하는 opioid 수용체억제제. 알코올중독이나마약중독의치료제로 FDA 승인을받음. Naltrexone 은내인성 opioid 에의한 POMC 뉴런의억제를차단함으로써결과적으로 POMC 뉴런의흥분성을증가시켜식욕을줄이고음식섭취를줄임. Bupropion 은시냅스에서도파민 / 노르에피네프린의재흡수를방해하는약물. 항우울제혹은금연치료제로 FDA 승인을받음. Bupropion 은뇌에서세로토닌과도파민의수치를증가시켜음식섭취량을감소시키고, 에너지소비를증가시켜체중감소를유도함. Naltrexone SR/bupropion SR 는 2014 년 9 월 FDA 승인.
COR-I 대규모 3 상임상시험, 유럽의 34 개지역 1,742 명의성인 BMI 30 45 kg/m² 이거나고지혈증또는고혈압을동반한 BMI 27 45 kg/m² 인사람 위약 : NB32 (naltrexone 32 mg/bupropion 360 mg) : NB16 (naltrexone 16 mg/bupropion 360 mg) = 1 : 1 : 1 비율로무작위배정
Effect of Contrave on body weight
Adverse events in the safety population
COR-II COR-I 의후속연구 1,496 명의성인 BMI 30 45 kg/m² 이거나고지혈증또는고혈압을동반한 BMI 27 45 kg/m² NB32 (naltrexone 32 mg/bupropion 360 mg) : 위약 = 2 : 1 비율로무작위배정
COR-BMOD Behavior modification (BMOD) 을동반한 Contrave 치료효과 793 명의성인 위약 + BMOD : NB32 + BMOD = 1 : 3 비율로무작위배정
Liraglutide (Saxenda)
당뇨병치료제인 Victoza 는 liraglutide 1.2 mg, 1.8 mg 제형 비만치료제인 Saxenda 는 liraglutide 3 mg 주사제형, 1 일 1 회투여
SCALE Obesity and Prediabetes 대규모임상 3 상연구 당뇨가없는비만환자 3,731 명대상 BMI 30 kg/m 2 이거나고지혈증또는고혈압을가진 27 kg/m 2 인사람 일일 1 회 liraglutide 3.0 mg : 위약군 = 2 : 1 비율로무작위배정
Effect of liraglutide on body weight
Liraglutide and glucose levels during oral glucose-tolerance test and glycemic status
Adverse events in the study population
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