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1 Presenter Disclosure Linong Ji Consulting and lecture fee Eli Lilly, Bristol-Myers Squibb, Novartis, Novo Nordisk, Merck, Bayer, Takeda, Sanofi-Aventis, GlaxoSmithKline, Roche, Johnson & Johnson, boehinger ingelheim, Guangzhou Zhongyi Pharmaceutical,Roche Diagnostics Employee: Peking University people s Hospital Research Support: Guangzhou Zhongyi Pharmaceutical

2 Global Prevalence of Diabetes and Chinese Diabetes Medicine Linong Ji, M.D, Peking University People s Hospital, Beijing, China

3 Prevalence (%) of diabetes(20-79 years), 2010 and 2030 IDF Diabetes Atlas 4th edition

4 Number of people with diabetes (20-79 years), 2010 and 2030 IDF Diabetes Atlas 4th edition

5 Diabetes in China China now has 90 million people with diabetes Prevalence of diabetes increased from 2.5% in 1994 to 5.5% in 2000 Prevalence of prediabetes increased from 3.2% 7.3% during the same period The prevalence of diabetes was higher among urban residents than among rural residents (11.4% vs. 8.2%) Yang W, et al. N Engl J Med. 2010;362(12):

6 Prevalence (%) Prevalence of diabetes in urban India (Chennai) Prevalence % Prevalence % Semi-urban Ramachandran et al. Diabetes Care 2008

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8 Type 2 diabetes prevalence in the USA and Asia In the USA, the prevalence has doubled from 4% 8% over the past 40 years In China, the prevalence has tripled from ~1 0% 3 2% between Yoon KH. Lancet 2006; 368:

9 Economic development and prevalence of diabetes in selected Asian countries, Ramachandran A. Lancet 2010,

10 Type 2 diabetes incidence / population per year Time Trends in Type 2 Diabetes incidence among Japanese Children Type 2 diabetes Obesity Prevalence of obesity (%) Kitagawa T et al. Clin Pediatr 1998

11 Diabetes is a public health emergency emerging in slow motion Ban Ki-Moon, United Nations Secretary-General

12 2010: The Next Step UN Resolution on NCDs 2011: NCD Alliance Plan for the UN Summit

13 The history of Diabetes in Traditional Chinese Medicine The nomenclature of Xiaoke 100 B.C: Yellow Emperor s Classic of Internal Medicine Monograph of Xiaoke A.D :Treatise on Febrile and Miscellaneous Disease Sweet urine and its extensive development 545 A.D: Ancient And Modern Proved Formulae Integration of Xiaoke and diabetes 1368 A.D: The Integration of Traditional Chinese Medicine and Western Medicine Zhang et al. European Journal of Integrative Medicine 2010; 2 : 41 46

14 The Yellow Emperor s Classic of Internal Medicine (100BC) Chapter Elementary Questions, Strange Disease Nomenclature Xiaoke ( wasting-thirst) Symptoms Polydypsia, polyphagia, polyuria and weight loss Cause Consuming too much fatty, sweety, or rich food. It typically occurs among wealthy people Treatment Diet: you ask them to refrain from a rich diet, advice which they may resist Medicine: Eupatorium Fortunei, expelling the residue morbid qi (qi flows upward and then transforms into wasting-thirst )

15 Three stages of Xiaoke in The Yellow Emperor s Classics of Internal Medicine Nomenclatures Splenic-pureheat/Pi-dan(light degree) Center wastingthirst/zhong-xiao (moderate degree) Pure-heat wastingthirst/ Xiao-dan(severe degree) Understanding in western medicine Initial stage (pre-diabetes) Second stage (stage of attack) Third stage (stage of complications) Thirst Severe thirst Shedding of flesh Dominant symptoms Polyphagia Starvation Diabetic foot (gangrene) Fever Spleen and stomach heat Paralysis Dominant syndromes Yin deficiency and excess of liver Yang Yin deficiency and heat Collapse of yin and qi Zhang et al. European Journal of Integrative Medicine 2010; 2 : 41 46

16 Herb medicines prescribed in 30 TCM for diabetes Xie W, et al. Evid Based Complement Alternat Med. 2011;: Epub 2011 Mar 17

17 ---- five pill: 1.25 g, 1.25 mg of glibenclamide Modern Chinese Medicine for diabetes Background ---- Since 1960s, there was a movement of integrating TCM with western medicine Products: compound preparations of Chinese herbs combined with allopathic medicine Xiaoke Pill: ---- Since 1982, annual sale (2010) of bottles( 120pills/ bottles) ---- Herb components 1) Radix Puerariae;2)Radix Rehmanniae;3)Radix Astragali; 4)Radix Trichosanthis; 5) Stylus Zeae Maydis;6)Fructus Schisandrae Sphenantherae;7)Rhizoma Dioscoreae ---- Mother formulas: Yuquan San, Dr. Jiebing Zhang (1563 一 1640) Xiaoke Fang, Dr. Zhenheng Zhu ( ) ----Western Medicine: glibenclamide

18 Modern evidence of Traditional Chinese Medicine for Diabetes Sixty-six randomized trials, involving 8302 participants Sixty-nine different herbal medicines Conclusion herbal medicines should not be recommended for routine use in diabetic patients of type 2 diabetes until we get scientifically sound trials Larger, well-designed trials is needed to establish the necessary evidence Liu JP. et al. Cochrane Database Syst. Rev. 2004;(3):CD003642

19 Previous clinical studies on Xiaoke Pill Study design Outcomes(proportion of glucose or HbA1c below certain levels ) Safety Renfenence RCT open label control centers Length (Weeks) Subjects (N) HbA1c FPG PPG Symptoms Hypoglycemia adverse effects Zhao YC, Hou M. Xiaoke Wan in treatment of 200 cases of type 2 diabetic patients. Changchun Zhong Yi Xue Yuan Xue Bao 1998;14:15. Zhang HZ. Clinical observation into Xiaoke Wan in the treatment of 86 cases of type 2 diabetic patients. Zhong Yi Yao Yan Jiu 1999;15: Chen G, Ni YD, Lai XM, Liang HQ. Clinical study on Xiaoke Wan in treating type 2 diabetes mellitus with Qi and Yin Defiency. Zhong Yao Xin Yao Yu Lin Chuang Yao Li 2003;14: Zhou R, Guo JJ, Yin CM, Li TK. Clinical observations of Xiaoke Wan in treatment of type 2 diabetic patients (Qi and Yin deficiency zheng). Zhongguo YaoWu Yu Lin Chuang 2003;3: glibenclamide single No data No data glibenclamide single No data No data glibenclamide mild/ 2 in Xiaoke pill glibenclamide single No data No data Wu JL. Observations into the effects of Xiaoke Wan in treatment of diabetes. Shi Yong Zhong Xi Yi Jie He Lin Chuang glibenclamide and Meformin single No data No data

20 Research hypothesis Compared with glibenclamide, Xioke Pill is noninferior in glucose lowing Goal of fasting glucose control < 126mg/dl (7mmol/L)

21 Trial design Run-In 4 weeks Treatment period Xiaoke pill n=200 Drug naive Glibenclamide n=200 Patients Xiaoke pill n=200 Metformin Glibenclamide n=200 Clinical visits every 4 weeks for 48 weeks Randomization Double Blinded Double Dummy Study end

22 Outcomes Primary: change in HbA1c at 48 week Secondary outcomes included: Incidence & Rate of Hypoglycemia Proportion of patients with HbA1c < 6.5% at 48 week Time to reach HbA1c < 6.5% Change in FPG Changes in body weight, lipids, HOMA-S & HOMA-B Change in Symptom Score

23 Analysis Methods The analysis of efficacy was based on ITT population Supportive analysis was conducted with PP set The safety analysis was based on ITT population Missing data were imputed using 25 multiple imputations All analyses were adjusted for centre effects

24 Analysis Methods The analysis of non-inferiority was based on the difference of mean changes at 48 weeks from the baseline The inference of non-inferiority was based on the upper limit of 95% CI of mean difference in change, with 0.4% of HbA1c as the pre-defined margin of non-inferiority The incidence and rates of hypoglycemia were analyzed using mixed-effect logistic regression and zero-inflated negative binomial regression methods respectively

25 Score of TCM symptoms of diabetes Symptom Mild(1 point) Moderate(2 point) Severe(3 point) Dry mouth and throat Occasionally Some times Often Fatigue Able to do daily work Hard to do daily work Unable to do daily work Polyphagia and easily hungry Only happen before meal Happen at any time Happen at any time accompanied by hypoglycemia symptoms Thirsty for drink Increased water intake <500ml 500ml<Increased water intake <1000ml Increased water intake >1000ml Short of breath, lazy to talk Happen after heavy work Happen after daily work Happen at any time Vexation Occasionally Some times Often Feverish palms and soles Occasionally Some times Often Palpitation Occasionally Some times Often Insomnia 4h/day < Sleeping time < 6h/day 2h/day < Sleeping time <4h/day Sleeping time <2h/day Constipation Dry stool, defecate everyday Dry stool, defecate every 2-3days Dry stool, defecate >every 3 days Zheng X, ed. Principal Guideline For the Development of New Traditional Chinese Medicine. Beijing: China Medical Science Press; 2010.

26 Dose titration initial Maximal* Xiaoke pill 5 pills (contain 1.25 mg glibenclamide) 30 pills (contain 7.5 mg glibenclamide) Glibenclamide 1.25 mg/day 7.5 mg/day * Or maximal tolerable dose Double blind and double dummy

27 Dose adjustment every 4 weeks according to FPG levels FPG >7.0 mmol/l FPG mmol/l FPG < 4.4 mmol/l Addition of 5 pills of Xiaoke Pill and/or half tablet of Glibenclamide No adjustment Reduction of 5 pills of Xiaoke Pill and/or half tablet of Glibenclamide

28 Results

29 Patient disposition 1076 Patients screened 276 Excluded 241 Did not meet inclusion criteria 3 Were lost follow up 4 Had protocol violation 11Withdrew consent 17 Other reasons 800 Underwent randomization 400 Drug naïve group 400 Metformin group 200 Assigned to Xiaoke pills 200 Assigned to Glibenclamide 200 Assigned to Xiaoke pills 200 Assigned to Glibenclamide 16 Excluded for protocol violation at first visit 16 Excluded for protocol violation at first visit 11 Excluded for protocol violation at first visit 10 Excluded for protocol violation at first visit 184 remained in Xiaoke pills 184 remained in Glibenclamide 189 remained in Xiaoke pills 190 remained in Glibenclamide 31 Excluded 5 Had adverse event 17 Had protocol violation 6 Were lost to follow up 3 Withdrew consent 34 Excluded 2 Had adverse event 17 Had protocol violation 10 Were lost follow up 5 Withdrew consent 25 Excluded 18 Had protocol violation 5 Were lost follow up 2 Withdrew consent 30 Excluded 24 Had protocol violation 5 Were lost follow up 1 Withdrew consent 153 Completed the study 150 Completed the study 164 Completed the study 160 Completed the study

30 Baseline - Demographics Variable Drug naïve group Metformin group Xiaoke pill (n=184) Glibenclamide (n=184) Xiaoke pill (n=189) Glibenclamide (n=190) Age-yr 54±9 54±8 54±8 55±9 Male-no.% 104(56.5) 106(57.6) 100(52.9) 92(48.4) Patient in CTH-no.% 76(41.3) 74(40.2) 74(39.2) 76(40.0) Exercise-no.% 135(73.4) 147(79.9) 146(77.2) 156(82.1) Diet-no.% 138(75.0) 155(84.2) 157(83.1) 166(87.4) Weight-kg 67.1± ± ± ±11.0 Body mass index-kg/m ± ± ± ±3.1 Waist-Hip ratio 0.9± ± ± ±0.1

31 Baseline Biochemical Measurements Variable Drug naïve group Metformin group Xiaoke pill (n=184) Glibenclamide (n=184) Xiaoke pill (n=189) Glibenclamide (n=190) Total cholesterol mmol/l 4.99± ± ± ±0.94 High-density lipoprotein mmol/l Low-density lipoprotein mmol/l 1.1± ± ± ± ± ± ± ±0.87 Triglycerides mmol/l* 1.65 ( ) 1.79 ( ) 1.87 ( ) 1.87 ( ) Ratio of albumin to creatinine * 3.53 ( ) 3.16 ( ) 3.88 ( ) 3.94 ( ) ALT U/L * 20.4 (15, 30) 22 (15.1, 33) 23 (16, 34) 23 (16, 31) AST U/L * 21 (17, 27.5) 21 (17, 27.6) 21 (17, 28) 21 (17, 27.7) Score of TCM symptoms of diabetes 8 (6,9) 8.5 (6,10) 8.5 (7,12) 8 (6,11) *Median (Inter Quartile Range)

32 Primary outcomes

33 Distribution of HbA1c Baseline Mean: 7.9 % Mean at 48 weeks: 7.2 % Mean at 48 weeks: 7.2 % Drug Naïve Group Metformin Group Baseline Mean: 7.8 % Mean at 48 weeks: 7.3 % Mean at 48 weeks: 7.4 %

34 Distribution of FPG Drug Naïve Group Metformin Group Baseline Mean: 9.1 mmol/l Mean at 48 weeks: 7.7 mmol/l Mean at 48 weeks: 7.5 mmol/l Baseline Mean: 9 mmol/l Mean at 48 weeks: 7.7 mmol/l Mean at 48 weeks: 7.7 mmol/l

35 Changes in HbA1c Drug naïve group Metformin group Mean at 24 week (95% CI) Absolute change from baseline at 24 week Mean at 48 week (95% CI)- ITT Absolute change from baseline- ITT at 48 weeks Absolute change from baseline- PP at 48 weeks N(%) of patients reaching A1c <6.5% at 48 week Odds Ratio (95% CI) Xiaoke pill 6.84 (6.68, 7.01) (-1.39, -0.76) 7.20 (7.01, 7.39) (-1.06, -0.34) (-1.37, -0.37) Glibenclamide 6.77 (6.51, 7.03) (-1.41, -0.74) 7.18 (6.91, 7.45) (-1.05, ) (-1.09, -0.33) Difference in Mean Change (95% CI) 0.01 (-0.12, 0.13) (-0.20, 0.12) (-0.48, 0.16) Xiaoke pill 7.05 (6.86, 7.25) (-0.86, -0.45) 7.27 (7.04, 7.50) (-0.68, -0.22) (-0.58, -0.25) Glibenclamide 7.17 (6.93, 7.41) (-1.12, -0.43) 7.36 (7.15, 7.57) (-0.94, -0.23) (-0.93, -0.21) 49 (26.6) 43 (23.4) 38 (20.1) 36 (18.9) Difference in Mean Change (95% CI) 0.12 (-0.13, 0.38) 0.14 (-0.12, 0.39) 0.16 (-0.18, 0.49) 1.31 (0.81, 2.13) P= (0.75, 1.92) P=0.44

36 Secondary outcomes

37 Hypoglycemia Drug naïve group Metformin group Xiaoke pill Glibenclamide P value Xiaoke pill Glibenclamide P value Total hypoglycemia no. (%) 28 (15.2) 39 (21.2) 23(12.2) 29(15.3) Odd Ratio 0.62 (0.42,0.94) (0.43,1.35) 0.35 Average Rate/ Patient/ Year 2.61 (1.73) 3.00 (1.97) 1.91 (1.24) 3.76 (2.95) Rate Ratio 0.76 (0.48, 1.18) (0.20, 0.71) Mild hypoglycemia no. (%) 26(14.1) 38(20.7) 23(12.2) 28(14.7) Odd Ratio 0.59 (0.42, 0.82) (0.44,1.44) 0.45 Average Rate/Patient/Year 2.58 (1.50) 2.95 (1.90) 1.87 (1.25) 3.54 (4.01) Rate Ratio 0.76 (0.49, 1.18) (0.20, 0.78) Nocturnal hypoglycemia no. (%) 3(1.6) 4(2.2) 1(0.5) 8(4.2) Odd Ratio 0.75 (0.16, 3.33) (0.01, 0.98) Average Rate/Patient/Year 2 (1) 1.25 (0.5) (0.71) Rate Ratio

38 FPG at 48 weeks Drug naïve group Metformin group Xiaoke pill Glibenclamide Difference in Mean Change (95% CI) Xiaoke pill Glibenclamide Difference in Mean Change (95% CI) Mean at 48 week (95% CI) (7.32, 8.11) (7.22, 7.86) (7.41, 8.01) (7.41, 8.04) Absolute change from baseline (-1.79, -1.06) (-1.79, -1.06) (-0.39, 0.40) (-1.71, -0.90) (-1.87, -1.08) (-0.18, 0.51) N(%)of patients reaching FPG<7 mmol/l Odds Ratio (95% CI) 78 (42.4) 82 (44.6) 69 (36.5) 79 (41.6) 1.05 (0.70, 1.58) P= (0.48,1.08) P=0.11

39 BP and weight at 48 weeks Weight-kg Mean at 48 week (95% CI) Absolute change from baseline Xiaoke pill (65.76, 70.41) Systolic blood pressure - mm Hg Mean at 48 week (95% CI) Absolute change from baseline Drug naïve group Glibenclamide (65.41, 70.10) Difference in Mean Change (95% CI) Xiaoke pill (66.68, 71.29) Metformin group Glibenclamide (64.55, 71.28) Difference in Mean Change (95% CI) 0.99 (0.19, 1.79) 1.14 (0.90, 1.38) (-0.89, 0.59) 0.51 (0.08, 0.93) 0.83 (0.48, 1.18) (-0.71, 0.06) 126 (124, 128) Diastolic blood pressure - mm Hg Mean at 48 week (95% CI) Absolute change from baseline 126 (124, 129) 125 (123, 127) 128 (124, 131) 0.33 (-1.64, 2.29) 1.63 (-0.41, 3.69) (-2.97,0.35) (-2.54, 2.32) 0.82 (-2.07, 3.71) (-3.64, 1.78) 77 (75, 78) 77 (76, 79) 78 (76, 79) 78 (76, 79) (-2.17, 0.40) (-1.98, 0.91) (-2.33, 1.63) (-2.40, 0.44) (-1.64, 1.56) (-2.98, 1.10)

40 Lipids at 48 weeks Drug naïve group Metformin group Xiaoke pill Glibenclamide Difference in Mean Change (95% CI) Xiaoke pill Glibenclamide Difference in Mean Change (95% CI) Total cholesterol mmol/l Mean at 48 week (95% CI) Absolute change from baseline Low-density lipoprotein mmol/l Mean at 48 week (95% CI) Absolute change from baseline High-density lipoprotein mmol/l 4.95 (4.80, 5.11) 4.67 (4.51, 4.83) 5.21 (5.02, 5.39) 4.84 (4.64, 5.03) (-0.15, 0.11) (-0.54, -0.07) 0.28 (0.02, 0.54) 0.07 (-0.21, 0.34) (-0.28, 0.02) 0.20 (-0.10, 0.49) 2.96 (2.78, 3.15) 2.69 (2.54, 2.84) 2.88 (2.69, 3.08) 2.79 (2.62, 2.97) (-0.38, -0.07) (-0.51, -0.23) 0.15 (-0.03, 0.32) (-0.22, 0.06) (-0.46, -0.16) 0.23 (0.06, 0.40) Mean at 48 week (95% CI) Absolute change from baseline 1.06 (1.00, 1.12) 1.05 (1.00, 1.10) 1.07 (1.01, 1.13) 1.12 (1.07, 1.16) (-0.11, -0.04) (-0.11, -0.02) (-0.06, 0.03) (-0.07, 0.03) (-0.10, 0.001) 0.03 (-0.03, 0.09) Triglycerides mmol/l Mean at 48 week (95% CI) Absolute change from baseline 1.97 (1.79, 2.14) 2.03 (1.83, 2.23) 2.43 (2.09, 2.77) 1.87 (1.70, 2.05) (-0.30, 0.06) (-0.58, -0.06) 0.20 (-0.09, 0.49) (-0.51, 0.22) (-0.57, -0.20) 0.24 (-0.24, 0.72)

41 HOMA and Score at 48 weeks HOMA-IR Mean at 48 week (95% CI) Absolute change from baseline HOMA- B Xiaoke pill Drug naïve group Glibenclamide Difference in Mean Change (95% CI) Xiaoke pill Metformin group Glibenclamide 3.26 (2.72, 3.80) 3.62 (3.17, 4.06) 3.51 (3.10, 3.91) 3.27 (2.96, 3.58) Difference in Mean Change (95% CI) (-1.34, -0.33) (-1.26, 0.14) 0.28 (-0.55, 1.11) (-0.95, 0.34) (-1.09, -0.35) 0.41 (-0.28, 1.10) Mean at 48 week (95% CI) (32.94, 64.80) (54.69, 75.21) (50.66, 59.51) (49.18, 71.13) Absolute change from baseline (12.21, 28.80) (14.40, 35.14) (-18.28, 9.74) (12.51, 20.99) (12.01, 30.85) (-14.75, 5.39) Score of TCM symptoms of diabetes Median (IQR) at 48 week Absolute change from baseline 2 (1,4) 4 (3,5) 3 (2,4) 3.5 (2,5) (-6.4, -4.9) (-5.46, -3.89) (-2.08, 0.15) (-7.10, -5.65) (-5.4, -4.03) (-2.66, -0.64)

42 Safety data

43 Adverse Events Event Treatment Naïve Group Metformin Group Xiaoke Pill Glibenclamide p Xiaoke Pill Glibenclamide p Urinary tract Infection 5 (2.7) 4 (2.2) (1.6) - Upper Respiratory Tract 9 (4.9) 10 (5.4) (7.9) 8 (4.2) 0.14 Infection Elevated ALT/AST - 1 (0.5) - 6 (3.2) 3 (1.6) 0.34 Dyslipidemia 18 (9.8) 18 (9.8) 1 21 (11.1) 11(5.8) 0.06

44 Summary of Findings Xiaoke Pill is non-inferior in glucose lowing as compared with glibeclamide There was no evidence of addition benefit from Chinese tradition medicine in terms of glucose lowing Treatment with Chinese traditional medicine was associated with lower incidence and rate of hypoglycemia

45 Summary of Findings No clinically meaningful differences were observed in body weight, lipids and HOMA estimates TCM in Xiaoke Pill do not have impects on other pathophysiological changes associated with type 2 diabetes The TCM diabetes Symptom scores were improved in patients treated with Xiaoke Pills

46 Acknowledgements Participating center of Evidence-Based Medical Research of Xiaoke Pill China Academy of Chinese Medicial Sciences Guang anmen Hospital, Beijing ; Peking University School of Public Health, Beijing ; Sichuan University West China Hospital, Chengdu ; The First Hospital of Hebei Medical University, Shijiazhuang ; The Third Affiliated Hospital of Peking University of Traditional Chinese and Western Medicine, Beijing ; The First Affiliated Hospital of Chongqing Medical University, Chongqing ; The Central Hospital of China Aerospace Corporation, Beijing ; China Meitan General Hospital, Beijing ; The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou ; Shanghai University of Traditional Chinese Medicine Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai ; Beijing University of Traditional Chinese Medicine Dongfang Hospital, Beijing ; Zhongshan University Sun Yai-sen Memorial Hospital, Guangzhou ; General Hospital of PLA Second Artillery, Beijing ; Peking University First Hospital, Beijing ; The Second Affiliated Hospital of Chongqing Medical University, Chongqing ; Nanjing Hospital of Traditional Chinese Medicine, Nanjing ; The Second Xiangya Hospital of Central South University, Changsha ; Shanghai Jiaotong University Ruijin Hospital, Shanghai ; Queensland Clinical Trials & Biostatistics Centre, School of Population Health, University of Queensland, Australia. Fund: National Basic Research Program of ; National High Technology Research and Development Program, and Guangzhou Zhongyi Pharmaceutical