PAGE 1 18-NOV-2016 SCIENTIFIC STUDY REPORT Study Title: Real-Life Effectiveness and Care Patterns of Diabetes Management The RECAP-DM Study 1 EXECUTIVE SUMMARY Introduction: Despite the well-established association between elevated haemoglobin A1C (HbA1C) levels and increased risks of microvascular and macrovascular complications in patients with type 2 diabetes mellitus (T2DM), evidence suggests that the majority of T2DM patients are not at HbA1C goal according to recommendations of consensus treatment panels. This study was undertaken to assess the level of glycemic control in real life practice settings in patients with T2DM.who had been treated with metformin monotherapy and initiated combination therapy with either a sulfonylurea or a glitazone three years prior to study enrolment, according to treatment goals recommended by national and international clinical practice guidelines in seven European countries. Methods: This was an observational, cross-sectional multicenter study with retrospective medical chart review conducted in Finland, France, Germany, Norway, Poland, Spain and UK. Included in the study were T2DM patients with a healthcare provider visit during an enrolment period between June 2006 to February 2007 who had added a SU or a TZD to metformin monotherapy between January 2001 and January 2006 (i.e. index date) and who had at least one hemoglobin A1C (HbA1C) measurement within 12 months before the visit date. Case report forms were used to collect demographic and clinical information from medical charts. The key study outcome was the proportion of patients with adequate glycemic control (defined according to the International Diabetes Federation as HbA1C < 6.5%) using the most recent HbA1C measurement before the visit date.
PAGE 2 18-NOV-2016 Key Results For the 2023 patients that met inclusion/exclusion criteria, mean age at the index date was 60.4 years, 45.3% were female, 1.5% had a history of microvascular complications, and 24.0% had a history of macrovascular complications of diabetes. The mean HbA1C level was 8.1%, and 92.7% of patients were not at HbA1C goal prior to the index date. Following addition of either an SU or a TZD, the mean HbA1C was 7.2% with 25.5% of patients being at HbA1C goal based on the most recenthba1c measurement before the visit date. For the rest of the patients 49.0% had HbA1C between 6.5% and 7.6%, while 25.6% of patients had HbA1C values greater than 7.6%. Relative to those not at goal, patients at HbA1C goal had significantly (p < 0.05) lower HbA1C (7.6% vs. 8.2%) prior to index date, were less likely to report a history of macrovascular complications (20% vs. 26%) and were more likely to report physical activity three to five times a week (29% vs. 23%). Key Conclusions In this study of T2DM patients from seven European countries, approximately one quarter were at HbA1C goal. The findings are in line with prior studies documenting that in general patients with T2DM are not treated to consensus HbA1C targets. 2 VALUE TO THE FRANCHISE THE STUDY DEMONSTRATES THE SIGNIFICANT UNMET NEED AMONG T2DM PATIENTS. THE STUDY HIGHLIGHTS THE NEED OF IMPROVING CARE MANAGEMENT IN DIABETES AS WELL AS OF DEVELOPING NEW AND EFFECTIVE THERAPEUTIC AGENTS. EM recommendations for use of the platform The study demonstrates that T2DM is a progressive disease with poor glycemic control even after treatment intensification. The path to better glycemic control would include better patient engagement and adherence to therapy, enhanced provider involvement in care management, and improved medications.
PAGE 3 18-NOV-2016 3 INTRODUCTION The association between elevated hemoglobin A1C (HbA1C) levels and increased risks of microvascular and macrovascular complications in patients with type 2 diabetes mellitus (T2DM) is well established. With the aim of improving overall outcomes among T2DM patients, consensus treatment panels have set aggressive HbA1C targets spurred on by clinical findings and epidemiologic studies. However, evidence suggests that the majority of T2DM patients are not at HbA1C goal according to recommendations of consensus treatment panels. This has been reported even after treatment intensification with insulin. This study was undertaken to assess the level of glycemic control in real life practice settings in patients with T2DM.who had been treated with metformin monotherapy and initiated combination therapy with either a sulfonylurea or a glitazone three years prior to study enrolment, according to treatment goals recommended by national and international clinical practice guidelines in seven European countries. The study contributes in the literature by employing a consistent methodology in assessing glycemic control across countries in patients who were treated with combination oral antihyperglycemic agents as a result of inadequate glycemic control on metformin monotherapy. 4 METHODS The Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) study was an observational, cross-sectional multicenter study involving patients with T2DM receiving oral antihyperglycemic treatment in Finland, France, Germany, Norway, Poland, Spain and UK. Included in the study were T2DM patients identified from medical charts at participating endocrinology, diabetology and general practice clinics. Study centers were selected randomly from a list comprising a convenience sample of physicians from each country. Eligible patients were identified during an enrollment period between June 2006 and February 2007. Identified patients were required to be at least 30 years old, to have added a SU or a TZD to metformin monotherapy between January 2001 and January 2006 (i.e. index date) and to have at least one hemoglobin A1C (HbA1C) measurement within 12 months before the visit date. Excluded were patients with T1DM; pregnant women, including those with gestational diabetes; diabetes secondary to other factors (e.g., malnutrition, infection, surgery); and those who could not complete questionnaires or were participating in another clinical study. Participating patients were asked to sign an informed-consent form prior to enrollment. Both the informed-consent document and study protocol were reviewed and approved by local ethical review boards in each country. Case report forms were used to collect demographic and clinical information from medical charts such as age and sex, smoking status, alcohol use, physical activity, history of microvascular and cardiovascular events, time since diabetes diagnosis, and most recent HbA1C measurement within the year before the enrollment date. The key study outcome was the proportion of patients with adequate glycaemic control (defined according to the International Diabetes Federation as HbA1C < 6.5%) using the most recent HbA1C measurement before enrollment date.
PAGE 4 18-NOV-2016 5 OBJECTIVES REPORTED IN THIS MEMO Primary Objectives This study aimed to assess the level of glycemic control in real life practice settings in patients with type 2 diabetes who had been treated with metformin monotherapy and initiated combination therapy with either a sulfonylurea or a glitazone three years prior to study enrolment, according to treatment goals recommended by national and international clinical practice guidelines 6 RESULTS Demographics A total of 2,023 patients met the inclusion and exclusion criteria and participated in the study. The mean patient age was 60.4 years, and the mean body mass index was 31.8 kg/m2 (Table 1). Among all patients, 1.5% had a history of microvascular complications, and 24.0% had a history of macrovascular complications of diabetes. DM was diagnosed for mean 5.8 years. The mean A1C level was 8.1%, and 7.3% of patients were at A1C goal (<6.5%). Patients who used insulin during follow-up (n = 243), compared with who did not (n = 1,780), had similar baseline demographic and clinical characteristics, except for lower rates of A1C at goal: 3.3% vs 7.8% (Table 1). Disposition Recruitment and Duration of Study A convenience sample of randomly selected physicians was derived from endocrinology, diabetology, and general-practice clinics and offices in Finland, France, Germany, Norway, Poland, Spain, and the United Kingdom. Eligible patients were identified for participation in the study from June 2006 to February 2007. Safety Results: None to Report
PAGE 5 18-NOV-2016 Detailed Results Following the addition of either SU or TZD to metformin monotherapy, the average most recently measured A1C level was 7.2%, and 25.5% of patients had reached A1C goal (i.e. <6.5%). Patients who had not received insulin during follow-up, compared with patients who did received insulin therapy, had lower A1C levels (7.1% vs 7.8%), and almost 3 times higher rate of reaching A1C goal (27.6% vs 9.5%). A1C level ranged from 7.1% in Poland to 7.3% in Norway and the United Kingdom. The rate of reaching A1C goal ranged from 15.6% in Norway to 30.1% in France. (Table 2) Patients who did not reach A1C goal, compared with those who did, had higher baseline rates of cardiovascular comorbidities, family history of cardiovascular conditions, and macrovascular conditions, and higher baseline rates of weight-reducing treatment and no other treatment (Table 3). There was also a slight trend of lower rates of goal attainment in patients receiving treatment for hypertension or dyslipidemia, and lower rates in patients who reported less physical activity 7 DISCUSSION Glycaemic control was poor overall, despite the prevalent use of combination oral antihyperglycaemic therapy with or without insulin, in this European cohort of patients with T2DM. The average A1C level at study completion was 7.2%, which exceeds the target goal of <6.5% recommended by IDF. Only 25.5% of patients had reached A1C goal of <6.5% (IDF). A1C goal attainment was lower in patients with more aggressive therapy, perhaps reflecting greater disease severity. Patients who failed to reach A1C goal at study completion had higher rates of use of combination treatment, including insulin and insulin use at follow-up. As expected, high-risk patients, with a history of macrovascular disease, hypertension, or dyslipidemia, tended to have less glycaemic control. Patients with a macrovascular condition at baseline had a significantly reduced chance of A1C goal attainment, after adjusting for covariates (OR 0.674). Physical activity was associated with glycaemic control, with lower rates of activity reported in patients who failed to attain A1C goal. Limitations of the study There are several potential study limitations inherent in the study design. Causality cannot be determined conclusively, due to the observational nature of the study. Results may potentially be confounded by the use of cardiovascular medications. Finally, the use of a convenience sample of physicians to recruit patients for the study may undermine the external validity of our findings.
PAGE 6 18-NOV-2016 Appendix 1 1. Details of Statistical Methods Patient demographics and survey responses were summarized using descriptive statistics. Differences in patient reports of hypoglycaemia and A1C goal status at visit date were evaluated by t-tests (continuous variables) or chi-square tests (categorical variables). Wald s test statistic was used to examine an association between hypoglycaemic symptom severity and A1C goal status at visit date. Statistical significance was evaluated at α = 0.05.
PAGE 7 18-NOV-2016 2. Supplemental analyses Table 1: Baseline demographic and clinical characteristics, overall and by insulin use during follow up* Characteristic Overall (N=2,023) No insulin used during follow up (n=1,780) Insulin used during follow up (n=243) Age, yr 60.4 ± 10.4 60.7 ± 10.5 58.6 ± 9.8 Percent female 45.3 45.0 47.5 Current smoker 13.20 % 13.01 % 14.58 % Never used alcohol 29.68 % 29.64 % 29.96 % No regular physical activity 35.81 % 35.52 % 37.93 % Physical activity 3-5 24.38 % 24.47 % 23.71 % times/week Weight, kg 88.9 ± 18.8 88.5 ± 18.6 91.8 ± 20.3 Body mass index, kg/m 2 31.8 ± 6.7 31.7 ± 6.7 32.8 ± 6.7 Age at DM diagnosis, yr 54.7 ± 10.3 55.0 ± 10.3 52.7 ± 9.6 Duration of DM at index date, 5.8 ± 4.9 5.7 ± 4.8 6.0 ± 5.1 yr Duration on metformin prior to 2.8 ± 2.6 2.8 ± 2.6 3.0 ± 2.6 index date, yr A1C 8.1 ± 1.4 8.0 ± 1.4 8.6 ± 1.6 Percent at A1C goal 7.3 7.8 3.3 Fasting blood glucose, mg/dl 111.7 ± 87.0 112.9 ± 86.4 102.8 ± 91.5 Family history of myocardial 19.4 % 18.8 % 23.7 % infarction Family history of DM 47.4 % 47.2 % 49.0 % Comorbid ischaemic heart 14.1 % 13.6 % 17.8 % disease Comorbid coronary heart failure 2.7 % 2.6 % 3.03 % Comorbid myocardial infarction 5.3 % 4.9 % 8.23 % Comorbid stroke 2.5 % 2.4 % 3.03 % Macrovascular conditions 24.0 % 23.4 % 28.1 % Microvascular conditions 1.5 % 1.4 % 2.2 % Hypotensive therapy 67.2 % 66.6 % 71.8 % Lipid-lowering therapy 47.6 % 47.6 % 47.9 % Weight-reducing therapy 1.8 % 1.6 % 3.0 % No other treatment 22.3 % 22.3 % 22.2 % Total cholesterol, mmol/l 5.2 ± 1.3 5.2 ± 1.2 5.4 ± 1.5 HDL cholesterol, mmol/l 1.3 ± 0.6 1.3 ± 0.6 1.2 ± 0.4 LDL cholesterol, mmol/l 3.0 ± 1.1 3.0 ± 1.1 3.1 ± 1.1 Triglyceride level, mmol/l 2.2 ± 1.8 2.2 ± 1.7 2.6 ± 2.3 Systolic blood pressure 140.6 ± 16.5 140.3 ± 16.4 142.7 ± 17.6 Diastolic blood pressure 82.7 ± 9.7 82.4 ± 9.6 85.1 ± 9.9
PAGE 8 18-NOV-2016 DM, diabetes mellitus; HDL, high-density lipoprotein; LDL, low-density lipoprotein *Data are mean ± s.d. unless otherwise specified. A1C <6.5% as measured within 12 months prior to visit
PAGE 9 18-NOV-2016 Table 2: Change in A1C at study completion by country.* Current A1C level nearest study enrollment date, % A1C <6.5 at follow-up, % Duration from index date to current A1C, yr Duration with T2DM at A1C follow-up, yr Duration on OHA, yr Overall (N=2,023) 7.17 ± 1.14 No insulin used during follow up (n=1,780) 7.09 ± 1.09 Insulin used during follow up (n=243) 7.79 ± 1.31 Spain (n=493) 7.17 ± 1.25 France (n=169) 7.11 ± 1.01 UK (n=407) 7.30 ± 1.16 Norway (n=64) 7.34 ± 1.08 Finland (n=193) 7.18 ± 1.23 Germany (n=410) 7.12 ± 1.03 Poland (n = 293) 25.46 27.64 9.47 29.21 30.06 17.94 15.63 29.53 24.39 27.99 2.55 ± 1.56 8.3 ± 5.11 5.38 ± 3.03 2.39 ± 1.47 8.11 ± 5.06 5.20 ± 2.80 3.70 ± 1.71 9.68 ± 5.30 6.66 ± 3.09 2.63 ± 1.41 8.83 ± 5.15 5.28 ± 2.73 2.42 ± 1.69 8.54 ± 5.24 6.27 ± 4.33 2.56 ± 1.70 7.40 ± 4.80 5.11 ± 2.81 3.15 ± 1.59 8.82 ± 5.70 5.74 ± 2.99 2.88 ± 1.86 7.68 ± 4.02 5.54 ± 2.87 2.55 ± 1.42 9.59 ± 5.29 5.73 ± 2.88 7.06 ± 1.06 2.09 ± 1.41 7.01 ± 5.13 4.74 ± 3.06 T2DM, type 2 diabetes mellitus; OHA, oral antihyperglycaemic agents *Data are mean ± s.d.
PAGE 10 18-NOV-2016 Table 3: Comparison of demographic and clinical characteristics of patients who attain A1C goal vs. those who do not attain A1C goal* Patients with A1C > 6.5% at follow up (n = 1,508) Patients with A1C < 6.5% at follow up (n = 515) Age at index date, yr 60.4 ± 10.5 60.5 ± 10.2 Age at follow-up, yr 63.0 ± 10.6 62.9 ± 10.3 Percent female 45.2 % 45.4 % Current smoker 13.9 % 11.0 % Never used alcohol 29.9 % 29.0 % No regular physical activity 37.7 % 30.2 % Physical activity 3-5 times/week 22.9 % 28.8 % Patient weight at baseline, kg 88.8 ± 18.8 89.1 ± 18.9 Patient body mass index at baseline, kg/m 2 31.8 ± 6.3 32.0 ± 7.8 Age at DM diagnosis, yr 54.6 ± 10.3 54.9 ± 10.1 Years with DM diagnosis at index date, yr 5.8 ± 4.9 5.6 ± 4.6 Years on metformin prior to index date, yr 2.9 ± 2.6 2.7 ± 2.6 A1C at baseline 8.2 ± 1.4 7.6 ± 1.3 Percent at A1C goal at baseline 4.6 % 15.2 % Fasting blood glucose at baseline, mg/dl 111.4 ± 88.4 112.5 ± 83.2 Duration from index to current A1C measure 2.6 ± 1.6 2.4 ± 1.4 Duration with T2DM at follow-up 8.4 ± 5.2 8.0 ± 4.9 Duration on oral antihyperglycaemic agent 5.5 ± 3.0 5.1 ± 3.0 Family history of myocardial infarction 20.6 % 15.8 % Family history of diabetes 47.5 % 47.1 % Comorbid ischaemic heart disease at baseline 15.8 % 9.3 % Comorbid coronary heart failure at baseline 3.0 % 1.6 % Comorbid myocardial infarction at baseline 5.9 % 3.6 % Comorbid stroke at baseline 2.4 % 2.6 % Macrovascular conditions at baseline 25.5 % 19.6 % Microvascular conditions at baseline 1.5 % 1.6 % Hypotensive treatment at baseline 68.3 % 64.0 % Lipid-lowering treatment at baseline 48.4 % 45.5 % Weight-reducing treatment at baseline 1.7 % 0.2 % No other treatment at baseline 21.9 % 2.4 % Total cholesterol at baseline in mmol/l 5.2 ± 1.2 5.2 ± 1.3 HDL at baseline in mmol/l 1.3 ± 0.6 1.3 ± 0.4 LDL at baseline in mmol/l 3.0 ± 1.1 3.1 ± 11 Triglycerides at baseline in mmol/l 2.3 ± 1.8 2.1 ± 1.8 Systolic blood pressure at baseline 140.9 ± 16.4 139.6 ± 16.8 Diastolic blood pressure at baseline 83.0 ± 9.6 81.8 ± 9.8 *Data are mean ± s.d. unless otherwise specified. A1C <6.5% as measured within 12 months prior to visit