EFFICACY AND SAFETY OF COMBINATION TREATMENT VERSUS MONOTHERAPY IN OBESITY: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Shant Krikorian, Peter Haydaw, Khaled, Bahjri and Ike de la Peña Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University

INTRODUCTION RESULTS Table 3: Number of Adverse events Produced by Mono- vs. Combination Therapy • Obesity is a common disease that increases risk for cardiovascular diseases, cancer and other health Articles (Randomized Controlled Trial) Monotherapy Combination Treatment

problems. Table 1. List of Randomized Controlled Trials included in the Meta-analysis Chirinos 2010 (Simvast. vs Simvast./Ezetimibe) 0 1 Flippatos 2005 (Orlis vs. Orlis./Fenofib.) 1 1 • Pharmacotherapy is an important treatment modality for obesity, and combination therapy has RANDOMIZED CONTROLLED TRIAL REFERENCE Flippatos2 2005 (Fenofib vs. Orlis./Fenofib.) 1 1 Flippatos 2008 (Orlis. vs. Orlis./Fenofib.) - - emerged as an attractive therapeutic intervention, in view of the multifactorial etiology of the Simvastatin/Ezetimibe VS. Simvastatin Chirinos et al., 2010. Am Heart J. Flippatos2 2008 (Fenofib vs. Orlis./Fenofib.) - - disease. Naltrexone/Bupropion VS. Naltrexone or Bupropion Greenway, et. Al., 2009. J Clin Endocrinol Metab Florentin 2008 (Remonab. vs. Remonab/Fenofib) 1 1 Florentin2 2008 (Fenofib. vs. Remonab/Fenofib) 0 1 Canagliflozin/Phentermine VS. Canagliflozin or Phentermine Hollander et al., 2017. Diabetes Care • Combination therapy may increase risk of adverse events. Gadde 2007 (Zonisamide vs. Bupropion/Zonisamide) 7 10 Liraglutide/Metreleptin VS. Liraglutide Jensterle, et al., 2017. BMC Endocr. Disord • We conducted a meta-analysis to examine comparative efficacy and safety of FDA-approved Greenway 2009 (BUP vs. NB16) 24 40 Sibutramine/Orlistat VS. Sibutramine or Orlistat Kaya et al., 2004. Biomed Pharmacother Greenway2 2009 (BUP vs. NB32) 24 36 combination treatments vs. monotherapies for obesity. Greenway3 2009 (BUP vs. NB48) 24 36 Orlistat/Resveratrol VS. Orlistat or Resveratrol Paniagua, et al. 2016. Obesity Huerta 2014 (EPA vs. EPA /Lipoic acid) 0 0 Huerta2 2014 (a-Lipoic Acid vs. EPA /Lipoic acid) 0 0 Pramlintide/Metreleptin VS. Pramlintide or Metreleptin Ravussin et al., 2009. Obesity Jabbour 2018 (Exenatide vs. Exenatide/Dapaglif) - - METHODS Orlistat/Metformin VS. Orlistat Sari, 2004. Int. J. Obes. Relat Metab. Disord Jabbour2 2018 (Dapaglif. vs. Exenatide/Dapaglif) - - Jensterle 2017 (LIRA3 vs. LIRA3/MET2000) 6 8 Lorcaserin/Phentermine VS Lorcaserin Smith et al., 2017. Obesity 1- Electronic database and manual Kaya 2004 (Sibutramine vs. Orlis./Sibutramine) 14 15 Orlistat Vs. Orlistat/Fenofibrate Flippatos et al., 2005. Journal of Clinical Lipidology Kaya2 2004 (Orlis. vs. Orlis./Sibutramine) 19 15 search using the search terms: Paniagua 2016 (Orlis. vs. Orlis./Reserv.) 1 1 Remonabant or Fenobirate Vs. Remonabant/Fenofibrate Florentin et al., 2008. Expert opinion on Phar. Paniagua2 2016 (Reserv. vs. Orlis./Reserv.) 3 1 “combination therapy vs. monotherapy, Ravussin 2009 (Metrelep. vs. Metrelep/Pramlin) 35 56 Zonisamide Vs. Bupropion/Zonisamide Gadde et al., 2007. J Clin Psychiatry Ravussin2 2009 (Pramlin. vs. Metrelep.) 57 56 obesity, randomized controlled trails”, EPA or a-Lipoic Acid Vs. EPA /Lipoic acid Huerta et al., 2014. Obesity Sari 2004 (Orlis vs. Orlis./Metformin) 0 5 “combination therapy, monotherapy, Smith 2017 (LOR vs. LOR BID/Phen QD) 50 52 Exenatide or Dapagliflozin Vs. Exenatide/Dapagliflozin Jabbour et al., 2018. Diabetes Obes Metab. Smith2 2017 (LOR vs. LOR BID/Phen BID) 50 54 obesity, randomized controlled trails,” “co- Total Events 317 390 administration, monotherapy, obesity, randomized controlled trials

2- Article review and selection according Table 2: Mean weight change Produced by Mono- vs. Combination Therapy DISCUSSION & CONCLUSION to inclusion/exclusion criteria: Inclusion Criteria Exclusion Criteria • The meta-analysis showed a 2.04 kg (95% confidence interval 1.67-2.42) additional tytyty • Population BMI 27 • Behavioral weight loss produced by the combination treatments versus monotherapies. kg/m2, therapy/intervention s as the other • The incidence of treatment-related adverse effects was higher (58%) in the • Outcomes  3 intervention month-weight loss combination treatments vs. monotherapies (49%), but this difference did not reach in percentage, • <100 participants statistical significance. • Type of intervention • Non-RCTs only and control groups: • These data provide randomized-based trial evidence on the efficacy and safety of combination vs. • Non-published, monotherapy Non- English combination treatments for obesity. language

3- Meta-analysis and Forest Plotting, Analysis of Adverse Events • Random effects model was used to provide a summary of weight change before and after ACKNOWLEDGMENT

exposure to treatments. This study is supported by research funds provided by the • Data on adverse events were extracted from each study and pooled to determine the overall Loma Linda University School of Pharmacy incidence of adverse events in combination treatment versus monotherapy