Ying Qiu, PhD World Diabetes Congress 2013 Melbourne, Australia

1. Why Physicians Do Not Prescribe Initial Dual Therapy to Qualified T2DM Patients: A Survey Study in the US Ying Qiu, PhD World Diabetes Congress 2013 Melbourne, Australia

2. Disclosure • Ying Qiu is a current employee of Merck & Co. • Qiong Li is a former employee of Merck & Co. • Ravi Shankar is a current employee of Merck & Co. • Samuel S. Engel is a current employee of Merck & Co. • AsclepiusJT LLC (Jackson Tang, Chun-Po Steve Fan, Zhiyi Li) received funding from Merck & Co. • Kantar Health Germany(Mercedes Apecechea, Ruth Hegar) received funding from Merck & Co.

3. AACE/ACE recommend initialdual therapy for A1C between 7.6% and 9.0% The AACE/ACE pharmacologic recommendations are stratified by baseline A1C: • 6.5 ~ 7.5%: Initiate monotherapy • 7.6 ~ 9.0%: Initiate dual therapy- Metformin based dual therapy • > 9.0%: Initiate triple therapy or initiate insulin

4. In practice many physicians do not prescribe dual therapy for qualifying patients • A recent study using GE EMR database found that only 7.6% T2DM patients with an initial A1C of 7.6% to 9.0% received the recommended dual therapy within 30 days after diagnosis(Qiu etal., results presented at ADA 2012). • Many potential barriers existpreventing qualified patients from receiving the recommended treatment • Barriers may be caused by physician, patient, system, and drug related reasons.

5. The research objective is to better understand these barriers • What are physicians' reasons for not prescribing initial dual therapy in qualified T2DM patients per AACE/ACE guideline? • Are the reasons associated with any of the physician and patient characteristics (i.e. physicians’ specialty and patients’ age)?

6. We conducted a large US-based physician survey and patient chart review • Primary care physicians (PCPs) and specialists were randomly selected to participate in a web-based survey. • Each physician provided medical chart reviews for 4 randomly selected patients who were diagnosed with A1C between 7.6% and 9.0% after Jan 1, 2010 and initiated with metformin monotherapy after diagnosis. • Physician characteristics, along with key patient characteristics and lab measures, were collected. • The final analysis sample included 1,525 physicians and 5,995 patient records.

7. The physicians were asked to rate the relevance of eachreason on their decisions • 22 reasons on why initial metformin monotherapy was given instead of dual therapy • 12 physician-related reasons (e.g. “Metformin monotherapy is sufficient to improve glycemic control”) • 8 patient-related reasons (e.g. “Patient has mild hyperglycemia”) • 1 system-related reason (e.g. “Insurance of the patient does not cover the dual therapy medications” • 1 drug-related reason(e.g. “Long term safety profile of dual therapy is not clear”) • Physicians were asked to rate the relevance of each reason using a 5-point Likert scale: • 1-Most irrelevant • 2-Irrelevant • 3-Neutral • 4-Relevant • 5-Most relevant

8. The list of 22 reasons in the survey • Physician-related • Patient-related • Metformin monotherapy is sufficient to improve glycemic control • In my opinion metformin monotherapy has better efficacy compared to dual therapy • Monotherapy is easier to handle than dual therapy • I believe that monotherapy and changes in lifestyle (e.g. physical activity and dietary change) are enough for hyperglycemia control • I recommend monotherapy before considering dual therapy • I am not comfortable with dual therapies for T2DM in general • I am uncertain how to dose the dual therapy • Adjusting of dual therapy is too time consuming • I have concerns regarding the patient's noncompliance to the dual therapy • I am not aware of guidelines recommending initial dual therapy for T2DM • Recommendations are not clear, because there are so many of them • I disagree with the guideline recommendations for treating this patient • Patient has mild hyperglycemia • Patient has medication intolerance for dual therapy • Patient has fear of side effects with dual therapy • Cognitive burden of administering dual therapy is too high for this patient • Patients attitudes toward initial dual therapy are denial, passive or unrealistic • Patient has a short life expectancy • Patient expresses that dual therapy poses a high financial burden for him/her • Patient´s access to care is limited (e.g. long distance to practice, need assistance for transportation) • Drug-related • Long term safety profile of dual therapy is not clear • System-related • Insurance of the patient does not cover the dual therapy medications

9. Top 5 most relevant reasons (>50% answered relevant) for not initiating dual therapy • Based on 5-point Likert scale, shown as both categorical and continuous variable

10. 4 out of 5 of the top reasons were more relevant for PCPs than specialists (1/2) More PCPs responded relevant (i.e. higher value) than Specialists • Based on 5-point Likert scale, shown as continuous variable

11. 4 out of 5 of the top reasons were more relevant for PCPs than specialists (2/2) A higher percentage of PCPs responded relevant than Specialists • Based on 5-point Likert scale, shown as categorical variable

12. … and4 out of 5 of the top reasons were more relevant for young patients (1/2) 4 out of 5 of the top reasons were more relevant for young patients Whereas mild hyperglycemia was more relevant in elderly patients for not initiating dual therapy • Based on 5-point Likert scale, shown as continuous variable

13. … and 4 out of 5 of the top reasons were more relevant for young patients (1/2) Physicians responded 4 out of 5 of the top reasons as more relevant for young patients Whereas mild hyperglycemia was more relevant in elderly patients for not initiating dual therapy • Based on 5-point Likert scale, shown as categorical variable

14. For each of the top 5 reasons, we tested for association with physician/patient characteristics Step 1 Linear models To assess and estimate the associations without any adjustments of covariates and intra-physician correlation. Dependent variable: 5-point Likert response, as continuous variables Independentvariables: Physician specialty, Patient age group Step 2 Mixed linear models • To account for the intra-physician correlation induced by the hierarchical data structure, we included 2 physician-specific random effects. • Random intercepts: to account for physicians may have different understandings in each question. • Random slope for patient’s age: to account for physicians may have different clinical interpretations of patients’ age. Dependent variable: 5-point Likert response, as continuous variables Independent variables: Physician specialty, Patient age, other relevant physician and patient characteristics • Note: • It is common to analyze Likert response as continuous variable in survey analysis.1,2 • As a sensitivity analysis, we also treated Likert response as categorical variable and conducted Ordinal Logistic regression. The results lead to the same conclusion as the current methods • Hoti et al, Int J Clin Pharm 2013 • Raaijmakers et al. BMC Research Notes 2013

15. Result 1: From linear models Linear model showed that PCP patients and young patients were more impacted by the physician related reasons • Based on 5-point Likert scale, analyzed as continuous variable

16. Result 2: From mixed models • Other covariates included in the mixed model: • Physician: sex, age, race, years in clinical practice, practice region, practice type, institution setting, % time spent in direct patient care, A1C as the decisive factor for the choice, treatment guidelines followed, and awareness of AACE guideline • Patient: sex, race, BMI, disease duration, A1C, number of comorbid conditions and if any concomitant medication uses Mixed linear model also showed PCP patients and lowering age were more impacted by the physician related reasons, after controlling for covariates and the hierarchical data structure. • Based on 5-point Likert scale, analyzed as continuous variable

17. Study Limitations • The findings may not be generalized to other countries. The study was motivated by AACE/ACE treatment guideline; the survey data were collected among US physicians and patients. • Concordance with AACE/ACE is assumed. However, prescribing behavior may not be perfectly correlated with physician guideline preference. • Physicians’ responses may be affected by self-perception. The physicians might not want others to perceive that they avoid dual-therapy despite the guideline’s recommendations. A desire to justify the treatment decision might have biased the results. • Physician’s difficulty remembering patient details may also be a limitation. • Although the mixed linear models accounted for the intra-physician correlation as a result of the hierarchical data collection, the mixed models assume no physician-patient interactions.

18. Conclusion • 5 reasons (4 physician-related, 1 patient related) were identified as most relevant in physicians’ decision of not initiating dual therapy for qualified patients as recommended by the treatment guideline • “I recommend monotherapy before considering dual therapy” • “Metformin monotherapy is sufficient to improve glycemic control” • “Monotherapy is easier to handle than dual therapy” • “I believe that monotherapy and changes in lifestyle (e.g. physical activity and dietary change) are enough for hyperglycemia control” • “Patient has mild hyperglycemia” • The reasons were much more relevant in primary care physicians than specialists and more relevant for young patients than elderly patients. • Further research in treatment patterns should be conducted to support/confirm the findings.

19. Thank you! • Global Health Outcomes, Merck USA • Ying Qiu, PhD; Qiong Li, PhD; Ravi Shankar, MD; Samuel S. Engel, MD • Asclepius JT, LLC • Zhiyi Li; Chun-Po Steve Fan, PhD; Jackson Tang • Kantar Health Germany • Mercedes Apecechea, MD; Ruth Hegar

20. Appendix

21. Background – AACE/ACE Diabetes Algorithm for Glycemic Control Source: AACE COMPREHENSIVE DIABETES MANAGEMENT ALGORITHM 2013

22. Survey Design – Data Collection • 22 reasons on why initial MM was given instead of dual therapy

23. Why initial MM was given instead of dual therapy (n=5,995) • Based on 5-point Likert scale

24. Results – Why initial MM was given instead of dual therapy (PCPs vs. Specialist)

25. Results – Why initial MM was given instead of dual therapy (Young vs. Elderly)

26. Physician characteristics (n = 1,525)

27. Physician characteristics (PCPs vs. Specialist) (1/2)

28. Results – Physician characteristics(PCPs vs. Specialist) (2/2)

29. Patient characteristics (n= 5,995) (1/2)

30. Patient characteristics (n= 5,995) (2/2)

31. Patient characteristics: Young vs. Elderly by physician specialty (1/4)

32. Patient characteristics: Young vs. Elderly by physician specialty (2/4)

33. Patient characteristics: Young vs. Elderly by physician specialty (3/4)

34. Patient characteristics: Young vs. Elderly by physician specialty (4/4)

35. Why initial MM was given instead of dual therapy (Among PCPs - Young vs. Elderly)

36. Why initial MM was given instead of dual therapy (Among Specialists - Young vs. Elderly)