The role and place of pharmacotherapy in effective weight management

Transcription

1 The role and place of pharmacotherapy in effective weight management Gabriel I. Uwaifo, MD FACE, FACP Senior Clinical Research Scientist and Endocrinologist, Ochsner Diabetes and Weight Management Clinical Research Section, Frank Riddick Diabetes Institute, Department of Endocrinology, Diabetes and Metabolism, Ochsner Clinic Foundation Complexities of Why Medications?? Because the odds are heavily stacked against your patients otherwise Appetite and Energy expenditure Regulation AGRP: agouti-related peptide; α-msh: α-melanocyte-stimulating hormone; GHSR: growth hormone secretagogue receptor; INSR: insulin receptor; LepR: leptin receptor; MC4R: melanocortin-4 receptor; NPY: neuropeptide Y; POMC: proopiomelanocortin; PYY: peptide YY; Y1R; neuropeptide Y1 receptor; Y2R: neuropeptide Y2 receptor. Apovian CM, Aronne LJ, Bessesen D et al. J Clin Endocrinol Metab. 2015;100:

2 1. Discrimination and bias against obesity and obese patients 2. Physician/clinician ignorance 3. Economic factors 4. Policy/political barriers 5. Lack of advocacy for obese people 6. Modest effectiveness of obesity drugs and other non surgical strategies 7. Sordid past history What Drives the Large Care Gap (knowledge to care and need to access gaps) in Obesity? Challenges and Barriers to Care Misaligned perceptions of success Past failures Prescription coverage Clinician competence and confusion Patient engagement Limited advocacy Provider reimbursement Few effective treatment options Time constraints Difficult, emotional conversations Cultural stigma and bias Lack of clear guidelines Rx market history of withdrawals Obesity as a disease vs. condition Competing clinician priorities STOP Obesity Alliance. Available at: Care-Paper-FINAL.pdf. Forman-Hoffman V et al. BMC Family Practice. 2006;7:35. 2

3 The Obesity pharmacotherapeutic hall of shame Thyroid extracts, T4, T Dinitrophenol 1934 Amphetamine 1947 Rainbow pills (cocktail of amphetamines, digitalis, thyroid hormone, diuretics, laxatives, barbiturates etc) 1950 Fenfluramine 1997 Dexfenfluramine 1997 Ephedrine Phenylpropanolamine (PPA) Sibutramine (2010) Rimonabant (2011) Hydroxycut (2009 reformulated 2011) *** But obesity medications are not the only therapeutic options for chronic disease management with a checkered past OBESITY IS THE LAST BASTION OF SOCIALLY ACCEPTABLE BIGOTRY Dr Richard Atkinson; Former President of TOS, AOA and emeritus Clinical Prof of Bariatric medicine 3

4 The reality; Few People with Obesity are Treated in the U.S. ~80 million adults with obesity <1% receive a prescription (Rx) for Anti Obesity Medication in a given month ~195,000 people per year receive bariatric surgery Sources: CDC 2014 (adults is defined as >20yrs. American Heart Association. Statistical Fact Sheet 2013 Update: Overweight and Obesity. Accessed June 9, Understanding the Treatment Dynamics of the Obesity Market, IMS Database (NPA) Aug 31, 2014; ASMBS website, estimated number of bariatric surgeries, published July 2016; asmbs.org Keys to Medical Weight Management A little goes a long way (5-10% deficit of baseline BMI/Body weight/body fat) Need for Chronic disease management mentality (for both patient and care givers) Extremely time consuming, and frustrating Complexity of care Chronic disease requires chronic treatment Combination therapy is more effective than monotherapy Comprehensive Treatment High rates of recidivism Concept of disease management vs cure 4

5 Currently available therapeutic Options for obesity management Accept weight where it is Effectiveness Diet/Exercise/Lifestyle modification: 3-10% weight loss Drugs: 5-15% weight loss Medically Supervised/Combination of Diet/lifestyle mod + Drug: 10-20% weight loss Surgery/devices: 15-50% weight loss Low High A Guide to Selecting Treatments for obesity management Treatment Body Mass Index category Diet, physical activity, and behavior therapy With co-morbidity Pharmacotherapy With co-morbidity Surgery With co-morbidity + NIH The Practical Guide AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: 5

6 Principles of effective pharmacotherapy of obesity Start with low doses and gradually adjust as needed Need for long term therapy including active initiation phase (3-12mths) and long term maintenance phase. Need to be used as part of effective lifestyle and dietary interventions Need to recognise concept of responders and non responders. Combination therapy is more effective than single agent therapy Need for careful medication inventory and reduction/elimination of medication saboteurs. 6

7 Principles of antidiabetic therapy with co-exisiting obesity Select medications with their effect on weight in mind. Avoid insulin ( especially prandial insulin ) if at all possible. Use as little insulin as required to achieve optimal glycemic control. Use combinations of weight loss inducing antidiabetic medications if possible and appropriate. Consider addition of weight loss enhancing antidiabetic medications to treatment profile even if glycemic targets are already achieved. Reduce hypoglycemia prevalence, occurrence and duration as much as possible as the natural defensive response to its prevention and treatment oft involves excessive caloric intake.(~ 75/25% ratio of insoluble/soluble fiber). Increase dietary fiber content; daily goal of 25-45g daily to enhance satiety and reduce post prandial glycemic spikes. Encourage patients to supplement with pre and probiotics. Track patients weight as rigorously as glycemic indices in the course of follow up. If appropriate combine weight loss pharmaceuticals with antidiabetic medications to optimize both glycemic control and weight management. Principles of antidiabetic therapy with coexisiting obesity 7

8 Pharmacologic Treatments for obesity FDA approved for long term therapy (>2yrs) Orlistat Lorcaserin (Belviq) Phentermine/topiramate ER (Qsymia) Bupropion/naltrexone (Contrave) Metreleptin (in unique setting of leptin deficient obesity) Liraglutide (Saxenda) Off-label usage: Topiramate, Metformin, other GLP-1 agonists (exenatide, albiglutide, dulaglutide, lixisenatide, Semaglutide etc), Pramlintide/Amylin, Bupropion, Zonisamide, phentermine) Drugs Approved by FDA for Treating Obesity (short term: 3-6 mths); Continued Generic Name Trade Names DEA Schedule Approved Use Year Approved Diethylpropion Tenulate IV Short-term 1973 Phentermine Phendimetrazine Adipex, lonamin Bontril, Prelu-2 IV Short-term 1959 III Short-term 1961 Benzphetamine Didrex III Short-term 1960 *** Important alert; the ADD/ADHD medications and interaction/abuse potential; methyphenidate, dexmethylphenidate, dextroamphetamine, dextroamphetamine/amphetamine combo, lisdexamphetamine 8

9 Pharmacologic Treatments for obesity Pharmacologic Treatments for obesity; What is not approved, efficacious or safe Thyroid hormone preparations; levothyroxine, cytomel and so called natural thyroid preparations like armor thyroid Phenlypropanolamine (PPA) and ephedrine based products. Various amphetamine preparations (ADD and ADHD medications). Vitamin B 12 injections Caffeine based products Nicotine based products Sympathomimetics including alpha and beta agonists. HCG injections. Diuretics and emetics. Hormone based products including glucocorticoids (steroids), androgens (including testosterone etc), growth hormone etc 9

10 Future potential targets for new obesity pharmaceutical treatments Agonists/stimulators Adiponectin 2αMSH/MC4R Apolipoprotein A-IV Brain-derived neurotrophic factor/trkb receptor CCK/CCK-A receptor CNTF/axokine Cocaine- and amphetaimine-regulated transcript GLP-1/exendin-4 Human GH fragment (AOD9604) Insulin mimetics Leptin; leptin receptor Oxyntomodulin PYY Phosphatidylinositol 3-kinase Somatostatin β3, serotonin, norepinephrine, dopamine receptors Antagonists/inhibitors Acetyl CoA carboxylase Agouti-related protein 11βHSD1 Central CPT1 CRH receptor DP-IV Endocannabinoid receptor (rimonabant/sr141716a) Fatty acid synthase (cerulenin; C75) Galanin GIP Ghrelin Histamine receptor MCH NPY Orexin A and B Suppressor of cytokine signaling-3 Tyrosine phosphatase IB Korner J - J Clin Endocrinol Metab - 01-JUN-2004; 89(6): Orlistat; Xenical and Alli A locally acting lipase inhibitor Acts by inhibiting fat digestion and thus absorption from the bowels. Dose range mg TID Longest FDA approved medication for long term weight loss Remarkable safety profile;only prescription weight loss medication also available OTC Pregnancy category B Most noteable side effect; oily stools (~ 25%) Orlistat: current status in clinical therapeutics. McClendon KS, Riche DM, Uwaifo GI. Expert Opin Drug Saf Nov;8(6): Review. 10

11 Orlistat; Xenical and Alli The Xendos trial showed Orlistat had beneficial effects on other cardiometabolic surrogates beyond its effects on weight including blood pressure, glycemia, and lipids. Phentermine; Adipex and Lomaira The longest FDA approved pharmaceutical agent Most widely used prescription weight loss adjunct Available as generic and thus the cheapest weight loss adjunct for out of pocket pay. Dosing range 8mg to 37.5mg. Dosed either QD or TID (for Lomaira) It is a sympathomimetic amine anorectic. Pregnancy Category X, It is regulated DEA schedule 4 agent. Contraindicated in patients with coronary artery disease, arrythmias, active heart failure and uncontrolled hypertension Avoid co-administration with MAO-Is and amphetamine products 11

12 Phentermine; Adipex and Lomaira WEIGHT LOSS WITH PHENTERMINE 36 week trials: Wt loss % Wt loss Munro, et al kg -13.0% BMJ, 68 Steel, et al kg -12.8% (Practitioner, 73) Saxenda; Liraglutide GLP-1 receptor agonist/analog with 97% homology to native GLP-1 Dosing range from 0.6 to 3.0mg daily Recommended weekly dose escalation till maximun tolerable dose is reached. Side effect profile typical of GLP-1 analogs with special attention regarding MTC and pancreatitis 12

13 Saxenda; Liraglutide Associated improvement with other cardiometabolic surrogates Excellent profile of combination with other antidiabetic and weight loss medications as well as use in most comorbid states Cardiovascular end point benefits The Saxenda-Victoza dichotomy Saxenda; Liraglutide 13

14 Belviq; Lorcaserin Belviq; the second coming of Fenfluramine and Dexfenfluramine Belviq is a serotonin 2c receptor agonist. The dose range is 5-10mg BID for the regular preparation and 10-20mg QD for the XR form. Lorcaserin is believed to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic proopiomelanocortin neurons located in the hypothalamus. Belviq; Lorcaserin Important potential medication interactions to be aware of; the serotonin syndrome; Potentially with triptans, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), dextromethorphan, tricyclic antidepressants (TCAs), bupropion, lithium, and tramadol, 14

15 Contrave; naltrexone/buproprion Naltrexone HCL Bupropion HCL Dose escalation schedule; A total daily dosage of two CONTRAVE 8 mg/90 mg tablets twice daily (32 mg/360 mg) is reached at the start of Week 4. CONTRAVE is a combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant Morning Dose Evening Dose Week 1 1 tablet None Week 2 1 tablet 1 tablet Week 3 2 tablets 1 tablet Week 4 - Onward 2 tablets 2 tablets Contrave; naltrexone/buproprion Most common side effects; headaches, nausea and vomiting but special consideration for neuropsychiatric symptoms (including increased suicidal risk in patients with mood disorders), increased risk for seizures and increase in BP and HR. Particular utility in patients with emotional eating and with certain eating disorders especially binge eating and night eating disorder. 15

16 Qsymia; Phentermine/Topiramate ER The dosing schedule recommended is slow dose escalation with 2 week intervals between each dose change Phentermine HCl Topiramate Qsymia; Phentermine/Topiramate ER -The single most effective FDA approved pharmaceutical adjunct. -Regulated pharmacy access -REMS program required for prescribers 16

17 Off label medication use for obesity pharmacoptherapy Need for full disclosure to the patient and documentation Need for particularly close follow up with clinical and biochemical survielance **There is a huge need for more combination therapy clinical trials of longer duration Available published data for combination therapeutic regimens suggesting greater efficacy and duration of weight loss -For phentermine monotherapy, topiramate monotherapy -For phentermine and topiramate combo therapy -For off label antidiabetics associated with weight loss -For lorcaserin phentermine combo therapy (the new phen-fen). -For symlin-leptin combo therapy -For GLP-1-leptin combo therapy -For GLP-1-symlin combo therapy -For GLP-1-SGLT-2 antagonist combo therapy -For Caffiene-Ephedra OTC combo therapy There is accumulating published data of the utility of pharmacotherapy as a bridge for certain patients prior to bariatric surgery as well as for management of certain patients with post bariatric surgery weight recrudescence. 17

18 Concluding Remarks Like in most other chronic diseases pharmacotherapy is a critical part of effective long term weight management of obese patients. There are several available options for adjunctive medication use in combination with lifestyle interventions, dietary interventions and more invasive management strategies. As with much of obesity care underutilization of medication therapy is multifactorial in etiology with limited insurance coverage and thus access being a major factor. More studies are needed of combinatorial therapy which is known to be more effective than single agent therapy. Strong advocacy movements and political pressure is needed to change perceptions and bias surrounding obesity management as a whole and pharmaceutical management in particular for its full potential to be realized and for the care gap between knowledge, population needs and actual treated patients to be bridged. Bibliography and References Bray GA, Ryan DH. Medical therapy for the patient with obesity. Circulation 2012; 125:1695. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014; 311:74. Jensen MD, Ryan DH, Apovian CM, et al AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014; 129:S102. Kaplan LM, Golden A, Jinnett K, et al. Perceptions of Barriers to Effective Obesity Care: Results from the National ACTION Study. Obesity (Silver Spring) 2018; 26:61. Douketis JD, Macie C, Thabane L, Williamson DF. Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice. Int J Obes (Lond) 2005; 29:1153. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015; 100:342. Leslie WS, Hankey CR, Lean ME. Weight gain as an adverse effect of some commonly prescribed drugs: a systematic review. QJM 2007; 100:395. Ara R, Blake L, Gray L, et al. What is the clinical effectiveness and cost-effectiveness of using drugs in treating obese patients in primary care? A systematic review. Health Technol Assess 2012; 16:iii. Khera R, Murad MH, Chandar AK, et al. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis. JAMA 2016; 315:

19 THANK YOU VERY MUCH FOR YOUR KIND ATTENTION Questions???, Comments??? 19