Rationale: Objectives: Indication: Diabetes Mellitus, Type 2 Study Investigators/Centers: 300 physicians in 292 clinics Research Methods: Data Source:

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1 GSK Medicine: N/A Study No.: Title: A Korean, multi-center, nation-wide, cross-sectional, epidemiology study to identify prevalence of diabetic nephropathy in hypertensive patients with type 2 diabetes Rationale: Numerous studies have clearly demonstrated that strict blood pressure control is more beneficial in the diabetic than in the nondiabetic hypertensive patients. As a result, recently released guidelines set the target level of blood pressure below 130/80 mmhg in diabetic patients with hypertension. This indicates that more aggressive antihypertensive treatment is needed in diabetic hypertensive patients. Nevertheless, previous studies have found that blood pressure control rates in these patients are lower compared to nondiabetic patients with hypertension, and little is known on the difference in blood pressure control rates according to the stages of diabetic nephropathy and/or the stages of chronic kidney disease. In addition, the relationship between blood pressure control and albuminuria or renal insufficiency has not been extensively investigated in primary-care diabetic patients with hypertension. Objectives: The primary objective of this study was to assess the prevalence of microalbuminuria and macroalbuminuria as well as the frequency of renal insufficiency. Secondary objectives were aimed to elucidate the relationship between blood pressure control and albuminuria and renal insufficiency and to identify the independent factors associated with albuminuria and renal insufficiency. Indication: Diabetes Mellitus, Type 2 Study Investigators/Centers: 300 physicians in 292 clinics Research Methods: Data Source: All subjects were asked to complete a questionnaire to collect information on demography (age, gender), lifestyle data (alcohol consumption, smoking, and exercise), and family history of hypertension and cardiovascular disease. Anthropometrical data [weight, height, waist circumference, hip circumference, and body mass index (BMI)], medical history, and antihypertensive medication were also recorded by the primary physician. Study Design: Nationwide, Cross-sectional, Primary-care unit-based study Study Population: Type 2 Diabetes Mellitus patients (N=3712) Study Exposures, Outcomes: Refer to below Primary, Secondary outcomes Data Analysis Methods: All values are expressed as means standard deviations (SD) or percentages. Statistical analyses were performed using SAS (version 9.1; SAS Institute, Cary, NC). Results were analyzed using ANOVA, Student s t-test, or Chi-Square test for comparisons. Significant differences found by ANOVA were further confirmed by the Student s t-test with the Bonferroni correction. Limitations: N/A Study Results: Demographics/Baseline Characteristics Study Group Comparison Group Table 1. Demographic characteristics of patients (N=3,712) Mean SD or N (%) N/A(This is an epidemiology study) N/A(This is an

2 Age(yr) Male : Female 1,677 : 2,035 Height(cm) Weight(kg) Body mass index (kg/m2) Waist circumference(inch) Duration of diabetes(yr) Duration of hypertension(yr) Family history Diabetes 1,724 (46.4) Hypertension (39.2) Smoking Smoker 724 (19.6) Ex-smoker 703 (19.1) Non-smoker 2,260 (61.3) Drinker 1,394 (37.8) Diabetic complications 894 (24.1) Systolic blood pressure(mmhg) Diastolic blood pressure(mmhg) Heart rate(bpm) Anti-hypertensive drugs ARB or ACEi 2,841 (76.5) CCB 1,728 (46.6) Beta blocker 417 (11.2) Diuretics 1,600 (43.1) Others 204 ( 5.5) Blood pressure control Controlled 1,164 (31.4) Uncontrolled 2,548 (68.6) epidemiology study) Primary and Secondary Outcome(s) Primary: The prevalence of microalbuminuria, macroalbuminuria and the frequency of renal insufficiency Study Group Comparison Group Evaluation of Study Outcome N/A N/A N/A Table 2. Laboratory findings of patients (N=3,675) Mean SD or N (%) Glucose(mg/dL) HbA1C(%) Urinary ACR (mg/g) Serum creatinine(mg/dl) egfr(ml/min/1.73m 2 ) by MDRD formula by CG formula Albuminuria Normoalbuminuria 2,595 (70.6) Microalbuminuria 850 (23.1)

3 Macroalbuminuria 230 ( 6.3) Renal insufficiency by MDRD formula 1,188 (32.1) by CG formula 1,709 (46.2) Secondary: Relationship between blood pressure control and albuminuria and renal insufficiency and to identify the independent factors associated with albuminuria and renal insufficiency Relationship between blood pressure control and albuminuria Figure 1. Correlation between natural logarithmic values of urinary ACR(Albumin-to-Creatinine Ratio) and systolic blood pressure. Systolic blood pressure correlated significantly with the natural logarithmic values of urinary ACR (R=0.16, p<0.0001). Relationship between blood pressure control and renal insufficiency Table 3. Comparison between patients with controlled and uncontrolled hypertension Uncontrolled Controlled hypertension hypertension (N=1,164) (N=2,548) p-value Age(yr) < Sex < Male 475 (40.8) 1,202 (47.2) Female 689 (59.2) 1,346 (52.8) Height(cm) < Weight(kg) < Body mass index( kg/m2) <0.0001

4 Waist circumference(inch) <0.005 Duration of diabetes(yr) NS* Duration of hypertension(yr) NS Diabetic complications 268 (24.6) 607 (23.8) NS Systolic blood pressure(mmhg) < Diastolic blood pressure(mmhg) < Heart rate(bpm) <0.001 Anti-hypertensive drugs ARBor ACEi 893 (76.7) 1,948 (76.5) NS CCB 531 (45.6) 1,197 (47.0) NS Beta blocker 134 (11.5) 283 (11.1) NS Diuretics 490 (42.2) 1,110 (43.5) NS Others 66 ( 5.7) 138 ( 5.4) NS HbA1C(%) NS Urinary ACR(mg/g) <0.005 Serum creatinine(mg/dl) <0.05 egfr(ml/min/1.73m 2) by MDRD formula <0.005 by CG formula < CKD stage by MDRD <0.05 Stage 1 or (65.4) 1,749 (68.6) Stage 3~5 399 (34.6) 789 (31.4) Factors associated with albuminuira Table 4. Comparison between patients with normo-, micro-,and macroalbuminuria Normo- Micro- Macro- (N=2,595) (N=850) (N=230) p-value Age(yr) <0.05 Sex Male 1,156 (44.5) 384 (45.2) 112 (48.7) < Female 1,439 (55.5) 466 (54.8) 118 (51.3) Height(cm) NS* Weight(kg) NS Body mass NS index( kg/m 2 ) Waist circumference NS (Inch) Duration of diabetes(yr) <0.0001

5 Duration of hypertension(yr) < Diabetic complications 524 (20.2) 244 (28.7) 113 (49.3) < Systolic blood pressure < (mmhg) Diastolic blood pressure < (mmhg) Heart rate(bpm) <0.005 Anti-hypertensive drugs ARBorACEi 1,964 (75.7) 645 (75.9) 216 (93.9) <0.05 CCB 1,171 (45.1) 435 (51.2) 107 (46.5) <0.001 Beta blocker 291 (11.2) 90 (10.6) 34 (14.8) NS Diuretics 1,138 (43.9) 337 (39.6) 104 (45.2) NS Others 137 ( 5.3) 45 ( 5.3) 20 ( 8.7) NS Blood pressure control Controlled 880 (33.9) 223 (26.2) 50 (21.7) < Uncontrolled 1,715 (66.1) 627 (73.8) 180 (78.3) HbA1C(%) < Urinary ACR(mg/g) < Serum creatinine < (mg/dl) egfr by MDRD formula < by CG formula < CKD stage by MDRD Stage 1 or 2 1,863 (71.8) 538 (63.3) 86 (37.4) Stage 3~5 732 (28.2) 312 (36.7) 144 (62.6) < Table 5. Factors associated with the presence of micro-/macroalbuminuria (Model 1) Factor Odds-Ratio (95% CI) p-value Age(yr) 0.99 ( ) <0.05 Sex (Male vs. Female) 1.31 ( ) <0.005 Duration of diabetes(yr) 1.04 ( ) < Duration of hypertension(yr) 1.00 ( ) NS* Diabetic complications (Yes vs. No) 1.54 ( ) < Systolic blood pressure(mmhg) 1.02 ( ) < Diastolic blood pressure(mmhg) 1.01 ( ) NS Heart rate(bmp) 1.00 ( ) NS Usage of ARB or ACEi (Yes vs. No) 0.99 ( ) NS Usage of CCB (Yes vs. No) 1.27 ( ) <0.005

6 HbA1C(%) 1.34 ( ) < egfr by MDRD 0.98 ( ) < Table 6. Factors associated with the presence of micro-/macroalbuminuria (Model 2) Factor Odds-Ratio (95% CI) p-value Age(yr) 0.99 ( ) NS* Sex (Male vs. Female) 1.22 ( ) <0.005 Duration of diabetes(yr) 1.04 ( ) < Duration of hypertension(yr) 1.00 ( ) NS Diabetic complications (Yes vs. No) 1.60 ( ) < Heart rate(bpm) 1.01 ( ) NS Usage of ARB or ACEi (Yes vs. No) 0.99 ( ) NS Usage of CCB (Yes vs. No) 1.28 ( ) <0.005 Blood pressure control (Controlled vs. Uncontrolled) 0.64 ( ) < HbA1C(%) 1.33 ( ) < Presence of renal insufficiency (MDRD) (Yes vs. No) 1.79 ( ) < Factors associated with renal insufficiency Table 7. Comparison between patients without and with renal insufficiency based on egfr by MDRD Renal insufficiency (-) (N=2,510) Renal insufficiency(+) (N=1,188) p-value Age(yr) < Sex < Male 1,321 (52.6) 347 (29.2) Female 1,189 (47.4) 841 (70.8) Height(cm) < Weight(kg) < Body mass NS* index(kg/m2) Waist <0.05 circumference(inch) Duration < of diabetes(yr) Duration < of hypertension(yr) Diabetic complications 508 (20.3) 384 (32.4) < Systolic blood NS pressure(mmhg) Diastolic blood < pressure(mmhg)

7 Heart rate(bpm) <0.05 Anti-hypertensive drugs ARB or ACEi 1,904 (75.9) 918 (77.3) NS CCB 1,167 (46.5) 554 (46.6) NS Beta blocker 245 ( 9.8) 170 (14.3) < Diuretics 1,070 (42.6) 524 (44.1) <0.05 Others 126 ( 5.0) 77 ( 6.5) NS Blood pressure control <0.05 Controlled 761 (30.3) 399 (33.6) Uncontrolled 1,749 (69.7) 789 (66.4) HbA1C(%) <0.001 Urinary ACR(mg/g) < Serum < creatinine(mg/dl) Albuminuria < Normoalbuminuria 1,863 (74.9) 721 (61.4) Microalbuminuria 538 (21.6) 309 (26.3) Macroalbuminuria 86 ( 3.5) 144 (12.3) Table 8. Factors associated with the presence of renal insufficiency (MDRD) (Model 1) Factor Odds-Ratio (95% CI) p-value Age 1.07 ( ) < Sex (Male vs. Female) 0.34 ( ) < Height 1.01 ( ) NS* Weight 1.01 ( ) NS Waist circumference 0.99 ( ) NS Duration of diabetes 1.03 ( ) <0.005 Duration of hypertension 1.00 ( ) NS Diabetic complications (Yes vs. No) 1.37 ( ) <0.005 Diastolic blood pressure 0.99 ( ) NS Heart rate 1.01 ( ) <0.05 Usage of beta blocker (Yes vs. No) 1.50 ( ) <0.005 Usage of diuretics (Yes vs. No) 1.06 ( ) NS HbA1C 1.04 ( ) NS Urinary ACR 1.00 ( ) < Table 9. Factors associated with the presence of renal insufficiency (MDRD) (Model 2) Factor Odds-Ratio (95% CI) p-value Age 1.07 ( ) < Sex (Male vs. Female) 0.34 ( ) < Height 1.01 ( ) NS* Weight 1.01 ( ) NS Waist circumference 0.99 ( ) NS Duration of diabetes 1.03 ( ) <0.0005

8 Duration of hypertension 1.00 ( ) NS Diabetic complications (Yes vs. No) 1.42 ( ) < Heart rate 1.01 ( ) <0.05 Usage of beta blocker (Yes vs. No) 1.51 ( ) <0.001 Usage of diuretics (Yes vs. No) 1.05 ( ) NS Blood pressure control (Controlled vs. Uncontrolled) 1.11 ( ) NS HbA1C 1.03 ( ) N Presence of albuminuria (Yes vs. No) 0.57 ( ) < Conclusion: In conclusion, a significant proportion of primary-care Korean type 2 diabetic patients with hypertension had albuminuria (micro- or macro-) and/or renal insufficiency. In addition, more than two-thirds of these patients had poorly controlled blood pressure. Therefore, careful attention and more aggressive treatment of blood pressure is necessary in terms of preventing the development of albuminuria in hypertensive type 2 diabetic patients.