Integration of Pharmacotherapy in the Clinic

Wm Troy Donahoo MD Department of Clinical Weight Management Kaiser Permanente Colorado And Assistant Professor, Univ. of CO Denver Integration of Pharmacotherapy into Art

Fred Tomaselli Aspen Art Museum August 1- Oct 11, 2009

Fred Tomaselli, Super Plant, 1994. Psychoactive plant material, acrylic, and resin on wood panel, 74 x 54 inches. Hort family collection. Copyright the artist. Courtesy James Cohan Gallery, New York The “Failures” of Pharmacotherapy for Obesity Treatment Years of Use Walking is man's best medicine (Hippocrates) 460-357 BC, (2009) Thyroid hormone 1893-1950s Dinitrophenol 1930’s Amphetamine 1937-?? Rainbow Pills (thyroid, amphetamine, 1946-1960’s sedatives, digitalis, laxatives and diuretics) Fenfluramine 1965-1997 Phenylpropranolamine 1979-1998 Ephedrine ???-2003 Phentermine 1959- Sibutramine 1997- Orlistat 1999- With This History, What Would/Will the Ultimate Impact of the Magic Weight Loss Pill be?

Dissemination Step Concept % Impacted 50% of Clinics Use Adoption 50%

50% of Clinicians Prescribe Adoption 25%

50% of Patients Accept Medication Reach 12.5%

50% Follow Regimen Correctly Implementation 6.2%

50% of Those Taking Correctly Benefit Effectiveness 3.2%

50% Continue to Benefit After 6 Months Maintenance 1.6% BARRIERS TO IMPLEMENTATION AND DISSEMINATION Customer (health care provider and patient):

High cost ($130 per month for siburamine) Intensive time demands and high level of staff expertise required (provider and behavioral staff) Difficult to learn or understand and not packaged or “manualized” (medication use/side effects and behavior program) Not developed considering user needs Not designed to be self-sustaining Highly specific to particular setting Not modularized or customizable BARRIERS TO IMPLEMENTATION AND DISSEMINATION (cont.)

Clinical setting

Competing demands occur Program imposed from outside Finance or organizations are unstable Clients and setting have specific needs Resources are limited Time is limited Organizational support is limited Prevailing practices that work against innovation Perverse incentives or regulations that oppose change BARRIERS TO IMPLEMENTATION AND DISSEMINATION (cont.)

Characteristics of Research Design Used:

Not relevant, diverse, or representative: Sample of patients Sample of settings Sample of clinicians Failure to evaluate cost Failure to assess implementation Failure to evaluate maintenance Failure to evaluate sustainability

Glasgow RE, Marcus AC, Bull SS. Disseminating effective cancer screening interventions. Cancer 2004;101:1239-1250 RE-AIM FRAMEWORK FOR FOCUSING ON KEY ISSUES IN INTEGRATING RESEARCH INTO PRACTICE RE-AIM TO HELP PLAN, EVALUATE, AND REPORT STUDIES

R Increase Reach

E Increase Effectiveness

A Increase Adoption

I Increase Implementation

M Increase Maintenance

Glasgow, et al. Ann Behav Med 2004;27(1):3-12 PURPOSES OF RE-AIM

To broaden the criteria used to evaluate programs to include external validity and context. To evaluate setting issues relevant to program adoption, implementation, and sustainability. To help close the gap between research studies and practice by: ™ Informing design of interventions ™ Providing guides for adoptees ™ Suggesting standard reporting criteria to increase transparent reporting Barriers to Weight Loss Medication Use

• Providers are hesitant to treat obesity and utilize medications due to concerns around (lack of long-term outcomes), time limitations, and reimbursement issues • {Donahoo and Hill Obes Mgmt 3:193-195, 2007} • Low long term adherence to weight loss meds, often due to satisfaction/expectations • Need for multi-disciplinary intervention Can a Group visit model overcome these issues? • Using a group visit in chronically ill older individuals resulted in higher satisfaction, better quality of life, and greater self efficacy, as well as fewer admissions, ER visits resulting in costs of $41.80 PMPM less than controls • {Scott, J et al JAGS 52:1463, 2004} • Most studies found improvements in patient satisfaction, decreases in health service utilization, quality of care, quality of life for the patients, and physician satisfaction • {Jaber R JABFM 19:276, 2006}. • Results on improvements in healthy behaviors and self efficacy, physical function and depression, disease specific outcomes, and decrease in total cost of care have been mixed • {Jaber R JABFM 19:276, 2006}. Characteristics of a Group Visit Clinic

Jaber R JABFM 19:276, 2006 RE-AIM ELEMENTS: REACH Definition: The number, percent of target audience, and representativeness of those who participate. Example: • Kaiser Permanente Colorado is an integrated health care delivery system with 492,377 members in the Denver/Boulder area • 68,367 have BMI 30-40, 12,445 have BMI>40 • 15% referred to Weight Management • 1.7% in behavioral program • 0.45% have surgery (1.9% of BMI>40) • 0.2% using medications prior . With GV model increased to 0.45% Key Issues: Does program reach those at highest risk? Are different approaches or visit options required? RE-AIM ELEMENTS: EFFECTIVENESS

Definition: Change in temporally appropriate outcomes, and impact on quality of life and any adverse outcomes. Example: How does sibutramine work, what are the weight loss results of sibutramine in well conducted trials or meta- analyses, and who responds best?

Key Issues: Logic models can help to clarify anticipated effects. Sibutramine: Chemistry

A racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine, 1-(4-chlorophenyl)-N,N- dimethyl-α-(2- methylpropyl)-, hydrochloride, monohydrate

C17 H29 Cl2NO, mw = 334.33 Sibutramine: Pharmacology

Rapidly absorbed with extensive first-pass metabolism to M1 and M2 metabolites ƒ Metabolites are active ƒ Sibutramine itself is not active Inhibits reuptake of serotonin, norepinephrine, (and dopamine) ƒ Inhibition of DA reuptake is ~3x less potent than NE, 5-HT ƒ Does not increase release ƒ No anticholinergic or antihistaminergic action ƒ No monoamine oxidase inhibition Serotonin and Weight Loss Pharmacotherapy Fenfluramine and the POMC System

•Dexfenfluramine causes release of serotonin by disrupting vesicular storage 5-HT, and reversing serotonin transporter function •Dexfenfluramine shown to activate POMC neurons in the arcuate nucleus

•Acts via 5-HT2c receptors Science 297:609, 2002 The Effect of Sibutramine on Weight The STORM Trial

STORM Trail Lancet 356: 2119, 2000 Effect of Sibutramine, Meta-analyses

16-24 week studies

44-54 week studies

LOCF

Complete Ann Int Med 142:537, 2005

<70% f/u

Arch Int Med 164:994, 2004 Medication Plus Lifestyle Modification

Wadden et al NEJM, 353:2111, 2005 Who Responds Best? • Clinical • Re-treatment weight IJO 25:946, 2001 • Need for preauthorization Obes Res 13:86, 2005 • Behavioral • Restrained eating (neg) Pharm Res 5:159, 2005, IJO 29:208, 2005, Diab Obes and Metab 10:498, 2008 • Rorschach incr if eating by external stimuli J Personality Ass 82:158, 2004 or physical demand state Obes es 11:1391, 2003 • HRQL incr emotional role functioning and low vitality IJO 28:600, 2004 • Lack of cognative restraint and incr appetite (olanzapine) BMJ Psych 9:12, 2009 • Genetic • Guanine Nucleotide Binding Protein beta-3 (Gastroent 135:1142, 2008, Pharmacogen 13:453, 2003) • Phenylethanolamine N-Methyltransferase (Obes Res 11:415, 2003) • Solute Carrier family 6 member 4 (Clin GI and Hep 5:1829, 2007) RE-AIM ELEMENTS: ADOPTION

Definition: Number, percent and representativeness of settings and clinicians who participate.

Example: Guidelines are equivocal on sibutramine, insurance companies are slow to evolve on use of pharmacotherapy for health not cosmetics, no mortality data exist, PCPs overestimate side effects

Key Issues: Need to focus on “denominator” and barriers among non-users. Do initial adoptees include peer opinion leaders? Clinical Evidence • Medications (diethylproprion, mazindol, orlistat, phentermine, rimonabant, sibutramine) may promote modest weight loss (an additional 1-7 kg lost) in obese adults having lifestyle intervention compared with placebo, but they all can cause adverse effects • Diethylproprion, mazindol, and phentermine have been associated with heart and lung problems • Sibutramine has been associated with cardiac arrythmias and cardiac arrest case reports • Trade-off between benefits and harms • Surgery “Likely to be beneficial” Clinical Evidence BMJ Publishing 2008 Sibutramine and Blood Pressure

JAMA 286:1337, 2001 Sibutramine and the ANS

Healthy, normal weight men and women (BMI=23) Sibutramine (10 mg 26h before, 10 mg 14h before, 20 mg 2 hr before) versus placebo versus sibutramine and metoprolol (200 mg 2 h before) Sibutramine caused: ƒ Increased BP and heart rate ƒ Decrease in heart rate variability ƒ Increase in energy expenditure

Circulation 106:2459, 2002 RE-AIM ELEMENTS: IMPLEMENTATION

Definition: Extent to which a program or policy is delivered consistently, and the time and costs of the program. Example: Patients being asked about their lifestyle by their physician are more likely to feel supported, but getting to and through the right option is difficult.

Key Issues: Consistency across staff, program components, and time. Balance between fidelity and local customization. Provider Discussion andThe Impact Patient of PCP Support Communication •Level of support is influenced by communications with PCP •Of those who have discussed healthy eating and active living habits with their PCPs in the past year (39% of all members) •Satisfaction with level of support is 70% •Compared to 29% of those who have not discussed these topics

Q: How well does Kaiser Permanente support your efforts to eat healthy and be active?

Q: In the past 12 months, has your PCP or health care provider discussed healthy eating, active living or weight management with you?

Unpublished, n=416 (of 3000 or 15%) HEAL Survey 11/07 Macro-valueMacro-value ProcessProcess forfor WMPWMP Micro-valueMicro-value ProcessProcess forfor InitialInitial RxRx GroupGroup VisitVisit RE-AIM ELEMENTS: MAINTENANCE

Definition: Individual/member target: Long-term effects and attrition. Setting/clinician: Extent of discontinuation, modification, or sustainability of program. Example: British Columbia Canada, for both orlistat and sibutramine, 1-year persistence rates are <10% and 2-year persistence rates are 2%. (IJO doi:10.1038/sj.ijo.080363)

Key Issues: Does attrition bias results; qualitative approaches to understanding program adaptation. Micro-valueMicro-value ProcessProcess forfor RxRx GroupGroup VisitVisit Follow-upFollow-up RECOMMENDED PURPOSE OF TRANSLATION/EFFECTIVENESS RESEARCH

To determine the characteristics of interventions that can: Reach large numbers of people, especially those who can most benefit. Be widely adopted by different settings. Be consistently implemented by staff members with moderate levels of training and expertise. Produce replicable and long-lasting effects (and minimal negative impacts) at reasonable cost.

34 Pharmacotherapy in the Clinic and the Triple Aim

Improve the health of the population

Patient Enhance the Reduce, or at patient least control, the experience of per capita cost of care (access, care and reliability) Medication Group Visit Outcomes very preliminary data

Effectiveness Satisfaction I New GV F/U GV New 1:1 Intervention 3 month 6 month %weight %weight Liked the way the loss loss visit was done 8.8 + 1.5 8.7 + 1.2 9.4 + 1.0 Meridia + 5.0% 6.8% GV (n=79) Got Info/ support Meridia - GV needed 9.1 + 1.2 8.8 + 1.1 9.4 + 1.0 (n=18) 3.8% 4.4%

Info/ support given 8.8 + 2.1 8.8 + 1.2 9.6 + 0.8 when needed Convenience sample, self Satisfied with chosen to group or no group 9.2 + 1.2 8.9 + 1.2 9.7 + 0.8 visit AcknowledgementsAcknowledgements

ƒ Kaiser Permanente •Funding ƒ Natalie Talley, DNP • NIH R21-AT-2617-1 ƒ Josh Levy, RD, MS • NIH/NCRR Colorado CTSI ƒ Joni McGuire, DNP Grant Number UL1 ƒ Anthony Rossi MBA, MSHA RR025780 ƒ Russell Glasgow, PhD • KP Institute for Health Research ƒ Arne Beck, PhD • Univ of Colorado Denver • Ed Melanson PhD • Wendee Gozansky, MD, MSPH