Characteristics of type2 diabetes in Asia and effect of an intensified multifactorial intervention on cardiovascular-renal outcomes (J-DOIT3)

Transcription

1 2018 International Congress of Diabetes and Metabolism Committee of international liaison session-diabetes in Asia Characteristics of type2 diabetes in Asia and effect of an intensified multifactorial intervention on cardiovascular-renal outcomes (J-DOIT3) Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Japan Takashi Kadowaki Friday Oct 12, 2018 Venue: Grand Hilton Seoul Hotel, Korea

2 The Japan Diabetes Society COI Disclosure Speaker:Takashi Kadowaki Funded research:msd Corporation, Daiichi Sankyo Co., Ltd., Novo Nordisk Pharma Ltd., Sanofi K.K., Takeda Pharmaceutical Co., Ltd. Endowed chair/community corporative course:takeda Pharmaceutical Co., Ltd., TERUMO Corporation, MSD Corporation, Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim Co., Ltd. Speaking fees: MSD Corporation, Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Kowa Pharmaceutical Co., Ltd., Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Taisho Pharmaceutical Co., Ltd.

3 Juliana C. N. Chan, MBChB, MD, Vasanti Malik, MSc, Weiping Jia, MD, PhD Takashi Kadowaki, MD, PhD, Chittaranjan S. Yajnik, MD, PhD Kun-Ho Yoon, MD, Frank B. Hu, MD, PhD Asians are more prone to develop T2D despite mild degree of obesity Genetic factors Epigenetic factors (exposure to poor nutrition in utero) Environmental factors(economic development, nutrition transition, sedentary lifestyles) Reduced insulin secretion Metabolically unhealthy obese phenotype due to abdominal adiposity JAMA, May 27, 2009 Vol 301, No

4 Risk factors for the development of type 2 diabetes in subjects with impaired glucose tolerance (Kadowaki T. et al. Diabetologia 26: 44-49, 1984) Early insulin response to glucose obesity Incidence of diabetes (%) z=3.49 p<0.01 n=200 5 n=88 DIRI/DBG(30min)<0.5 DIRI/DBG(30min) (year) (%) z=3.39 p< Relative body weight +30% n=72 n=216 Relative body weight < +30% 10 (year) Proportional hazard model analysis (Cox) 1 Decreased early insulin response to glucose 2 Obesity-induced insulin resistance 3 Family history of diabetes

5 Diabetes in Japanese : Lower insulin secretory capacity Serum insulin levels during OGTT NGT IGT DM Insulinogenic index Caucasian Japanese Caucasian Japanese NGT IGT DM (From Fukushima M & SeinoY Diabetes Res Clin Pract 2004 ) 5

6 Asians are susceptible to T2DM despite mild degree obesity due to reduced insulin Caucasians Asians BMI=30 BMI=25 Normal BMI=25 High insulin Low insulin DM IGT DM IGT 6

7 (Nature Genetics 2008) 7

8 GWAS in Japanese populations identified KCNQ1 as a novel T2D susceptibility gene -Millennium project- Genome-wide association with T2D rs rs rs Panel 2+3 Panel 1 (Japanese) Panel 2 (Japanese) Replication OR P-value Combined (Japanese) x10-29 KCNQ1 Panel 3 (Chinese ) Panel 4 (Korean) Combined (East Asian) x10-40 European 1.29 Combined x Multiple SNPs in KCNQ1 were associated with T2D in genome-wide level and confirmed in other ethnic populations OR (Nature Genetics 40:1092-7, 2008) 8

9 Comparisons of the GWAS in Caucasian and Japanese populations Caucasian Scott et al. Diabetes 2017 May case 26,676 (stage1) 36,614 control 132,532 (stage1) 155,150 reference panel 1000G phase1 (n=1,092) Novel 13 loci Common 4 loci Japanese Suzuki et al. Nature Genetics in revision 1000G phase3 (n=2,504) Novel 28 loci 24 loci were identified only in the Japanese GWAS 9

10 Pathway analysis of T2D GWAS results for Japanese and Europeans database Pathway name FDR Japanese GWAS (n = 191,764) KEGG maturity onset diabetes of the young (MODY) REACTOME regulation of beta cell development REACTOME regulation of gene expression in beta cells REACTOME signaling by NOTCH REACTOME developmental biology REACTOME NOTCH1 intracellular domain regulates transcription REACTOME regulation of insulin secretion European GWAS (n = 159,208) KEGG maturity onset diabetes of the young (MODY) KEGG type II diabetes mellitus REACTOME developmental biology REACTOME regulation of beta cell development KEGG ABC transporters REACTOME pre NOTCH transcription and translation KEGG prostate cancer MODY, βcell, developmental biology pathways were common in Japanese and Europeans Regulation of insulin secretion was significant only in Japanese (Suzuki K, Yamauchi T, Kadowaki T et al. Nature Genetics in revision) 10

11 Japanese accumulate visceral fat more easily than Westerners Mean values of subcutaneous fat and visceral fat (cm 2 ) 350 Westerners Japanese ± ± ± ±26.6 Area of subcutaneous fat Area of visceral fat Analyzed from the literature papers which clearly shows sectional areas of visceral fat and abdominal subcutaneous fat measured by using CT, as well as mean ages and races (Japanese males: 15 reports, Japanese females: 7 reports, Caucasian males: 10 reports, Caucasian females: 18 reports). Tanaka S. et al.:acta Diabetol.,40,S302,2003.

12 Epidemic of type 2 diabetes and its background in Japan and Asian countries Fat intake increased 4-fold in 50 years Increased 4-fold in 50 years to 23 million people Percent increase in diabetic patients Skeletal muscle Environmental factors High-fat diet / Sedentary lifestyle Liver Obesity / Accumulation of visceral fat Fat tissue Insulin resistance 40-fold Interaction Genetic factors Reduced insulin secretion Insufficient insulin action Onset of type 2 diabetes 6.8 mil. 690 万人 7.4 mil. 740 万人 Pancreas 万人 (about 1/2 of westerners) Number of patients with Diabetes mil. 9.5 mil. 950 万人 10.0 mil (Ministry of Health, Labour and Welfare) 12

13 Status of diabetes and metabolic syndrome and their complications in Japan Increased mortality Atherosclerosis:Stroke (n=1,370,000/year) MI (n=870,000/year), ASO etc Obesity x2 Metabolic Syndrome(MS) Visceral fat accumulation +Dyslipidemia +hypertension +Hyperglycemia MS: 9,200,000 MS at risk:9,800,000 Macroangiopathy x5 Development of Diabetes x4 Diabetes (n=10,000,000) Microangiopathy nephropathy retinopathy neuropathy Chronic renal failure (Initiation of dialysis:16,000/year) Blindness (3,000/year) Lower limb amputation (3,000/year) 13

14 J-DOIT (Japan Diabetes Outcome Intervention Trial) MHLW: Ministry of Health, Labor and Welfare JF-PIMRC: Japan Foundation for the Promotion of International Research Cooperation MHLW Funding JF-PIMRC Research leader Dr. Hideshi Kuzuya Research leader Prof. Masashi Kobayashi Research leader Prof. Takashi Kadowaki HCC HCC HCC HCC Clinic Clinic Clinic Clinic Hosp. Hosp. Hosp. Hosp. J-DOIT1 J-DOIT2 J-DOIT3 A 50% reduction in the conversion rate from IGT to DM A 50% reduction in the dropout rate from diabetes treatment A 30% reduction in the development of diabetic complications Prevention of diabetes and its complications (Yazaki and Kadowaki Nat Med 2006) 14

15 Subjects The primary outcome The Secondary outcomes Test period J-DOIT3 Overview Type 2 diabetes with high blood pressure or dyslipidemia(age 45-69) HbA1c 6.9% n=2542, Primary prevention 89%, Secondary prevention 11% Death, Myocardial infarction, Stroke, Revascularization NCT The main secondary outcome: Death, Myocardial infarction, Stroke Other Secondary outcomes:the onset or progression of renal disease, Lower limb amputation, the onset and progression of retinopathy Follow-up period is until the primary endpoint reaches 250 cases Therapeutic goal Intensive therapy group n = 1271 Conventional therapy group n = 1271 Blood glucose HbA1c < 6.2% HbA1c < 6.9% Blood pressure < 120 / 75mmHg < 130 / 80mmHg LDL-C < 120mg/dL LDL-C < 80mg/dL Lipid (*LDL-C < 100mg/dL) (*LDL-C < 70mg/dL) * History of CHD (Yazaki Y, Kadowaki T Nature Medicine 2006, Ueki K, Kadowaki T. BMJ Open Diabetes Research & Care 2017) 15

16 Duration of Study and Frequency of Visits - The median duration of study was 8.5 (IQR 7.3, 9.0) years. - During the trial, patients receiving intensive therapy attended an average of 70 visits, as compared with 63 visits for patients receiving conventional therapy. 10 Duration of study of recent RCTs in type 2 diabetes [year] 5 0 UKPDS ACCORD VADT Steno-2 ADVANCE ADDITION -Europe J-DOIT3 Ueki K, Sasako T, Kadowaki T and the J-DOIT3 Study Group.The Lancet Diabetes & Endocrinology 2017 Dec;5:

17 Lifestyle Modifications and Self-Monitoring Conventional Diet therapy Total energy intake, kcal/kg according to daily activity Exercise therapy Smoking cessation Education Selfmonitoring Provided with an accelerometer In accordance with the guideline [14] In accordance with the guideline [14] Provided with a BP manometer Intensive Total energy intake, 25 kcal/kg in those with BMI 25, 27 kcal/kg in those with BMI <25 Provided with an recordable accelerometer, and encouraged to report on the calories consumed as well as the number of steps taken every day Instructed to persevere in their smoking cessation practice and to report at their regular hospital visits on the number of cigarettes smoked Provided with smoking-cessation aids, if necessary A core program and a post-core program intended to improve lifestyle habits are to be implemented to ensure lifestyle factors are improved Provided with a blood glucose meter and a BP manometer Ueki K, Kadowaki T. BMJ Open Diabetes Research & Care 5, e000322,

18 Mean HbA1c during Intervention Group: P<0.001, Group difference: % (95% CI to -0.32). 7.2 % (Conventional) 6.8 % (Intensive) Ueki K, Sasako T, Kadowaki T and the J-DOIT3 Study Group.The Lancet Diabetes & Endocrinology 2017 Dec;5:

19 [%] Glucose-lowering agents in J-DOIT3 intensive therapy group Pioglitazone SU αgi Glinide GLP-1RA Biguanide DPP-4 inhibitor Insulin SGLT2 inhibitor 19

20 Comparison of incidence of severe hypoglycemia in large-scale RCT in the treatment of diabetes Incidence of severe hypoglycemia (% per yr) Conventional Intensive HbA1c(%) reached ACCORD ADVANCE VADT UKPDS J-DOIT3 In J-DOIT3, blood glucose was lowered to near-target values with much lower incidence of severe hypoglycemia Ueki K, Sasako T, Kadowaki T and the J-DOIT3 Study Group.The Lancet Diabetes & Endocrinology 2017 Dec;5:

21 Mean BMI during Intervention Group: P = 0.321, Group difference: 0.05 (95% CI to 0.15). Ueki K, Sasako T, Kadowaki T and the J-DOIT3 Study Group.The Lancet Diabetes & Endocrinology 2017 Dec;5:

22 Summary of the control status of risk factors HbA1c [%] Systolic BP [mm Hg] Diastolic BP [mm Hg] LDL-cholesterol [mg/dl] Mean at baseline Conventional Target Intensive Target Intensive Conventional Mean during intervention Ueki K, Sasako T, Kadowaki T and the J-DOIT3 Study Group.The Lancet Diabetes & Endocrinology 2017 Dec;5:

23 Marked reduction of vascular complications in diabetic patients treated according to the current guideline (conventional) as compared with a previous national study with similar patients background in Japan Incidence of myocardial infarction (% per yr) Incidence of stroke (% per yr) JDCS* J-DOIT3 JDCS* Conventional JDCS*:Registration ( ), Follow-up7.9yr J-DOIT3:Registration ( ), Follow-up8.5yr J-DOIT3 Conventional *Japan Diabetes Complications Study 23

24 Summary: Risk Reduction in the Intensive-Therapy Arm Risk reduction (compared to the conventional -therapy arm) Primary Outcome All-Cause Death Mortality Myocardial infarction Stroke Revascularization Components of Primary Outcome (Post-Hoc) Coronary Events Cerebrovascular Events Primary Outcome (adjusted) Main Secondary Outcome Death Myocardial infarction Stroke Secondary Outcomes Nephropathy Events Retinopathy Events Lower limb Vascular Events -19% p = % p = % p = % p = % p = % p = % p < % p = % p = 0.80 Ueki K, Sasako T, Kadowaki T and the J-DOIT3 Study Group.The Lancet Diabetes & Endocrinology 2017 Dec;5:

25 Cause of Death Cause -- no. (%) Conventional Intensive Malignant neoplasms 25 (2.0) 32 (2.5) Myocardial infarction 1 (0.1) 0 (0.0) Stroke 3 (0.2) 0 (0.0) Heart failure 1 (0.1) 0 (0.0) Liver failure 1 (0.1) 4 (0.3) Pneumonia 3 (0.2) 0 (0.0) Other infectious diseases 2 (0.2) 0 (0.0) Interstitial pneumonia 4 (0.3) 0 (0.0) Sudden death 2 (0.2) 2 (0.2) Accident 1 (0.1) 0 (0.0) Suicide 0 (0.0) 2 (0.2) Others 2 (0.2) 1 (0.1) Undetermined 3 (0.3) 8 (0.6) Total 48 (3.8) 49 (3.9) - None of the patients died of cardiovascular disease in intensive arms. Ueki K, Sasako T, Kadowaki T and the J-DOIT3 Study Group.The Lancet Diabetes & Endocrinology 2017 Dec;5:

26 Cumulative Incidence of Cerebrovascular Events (Post-Hoc) (Stroke and cerebral revascularization) Probability of Cumulative Incidence of Event Intensive therapy Conventional therapy HR, 0.42; 95% CI; 0.24 to 0.74; P= No. at Risk Number needed to treat = 47.6 at 8 years Years of Intervention Conventional Intensive Cerebrovascular Events Conventional Intensive Stroke Cerebral revascularization 3 2 Ueki K, Sasako T, Kadowaki T and the J-DOIT3 Study Group.The Lancet Diabetes & Endocrinology 2017 Dec;5:

27 Classification of stroke and risk factors 60 events Cerebral hemorrhage:5 Subarachnoid hemorrhage:1 Cerebral infarction:54 Lacunar:21 Unclassified/ Unknown:8 Atherothrombotic:21 Cardiac:4 Stroke was positively correlated with baseline characteristics such as age, prior history of CVD, smoking, BP, LDL-C and inversely correlated with HDL-C 27

28 Cumulative Incidence of Renal Events Probability of Cumulative Incidence of Event Intensive Conventional HR, 0.68; 95% CI; 0.56 to 0.82; P<0.001 Years of Intervention Conventional al Intensive First Events Normo- to microor macroalbuminuria Micro- to macroalbuminuria Doubling of serum creatinine End-stage renal failure Conventional Intensive Ueki K, Sasako T, Nangaku M, Kadowaki T: Unpublished results 28

29 Cox Regression Analysis on Renal Events: Landmark Analysis Variables at 1 year after randomization Hazard Ratio * ** 95% CI P Lower Upper Value Arm Conventional / Intensive Strata of risk Low / High <0.001 Low / Middle Smoking status at 1 year No / Yes BMI at 1 year HbA1c at 1 year [%] Systolic blood pressure at 1 year [mmhg] Diastolic blood pressure at 1 year [mmhg] HDL-cholesterol at 1 year [mg/dl] LDL-cholesterol at 1 year [mg/dl] Triglyceride at 1 year [mg/dl] * HR to the control category shown left to the slash, or HR per unit. Ueki K, Sasako T, Nangaku M, Kadowaki T: Unpublished results 29

30 Mean egfr during Intervention According to egfr at Baseline Baseline egfr 60mL/min/1.73m 2 Baseline egfr < 60mL/min/1.73m 2 Conventional Intensive Intensive Conventional Years of Intervention Years of Intervention Ueki K, Sasako T, Nangaku M, Kadowaki T: Unpublished results 30

31 Cox Regression Analysis on egfr Decline (Baseline egfr <60): Landmark Analysis Variables at 1 year after randomization Hazard Ratio 95% CI P Lower Upper Value Arm Conventional / Intensive Smoking status at 1 year No / Yes BMI at 1 year HbA1c at 1 year [%] Systolic blood pressure at 1 year [mmhg] Diastolic blood pressure at 1 year [mmhg] HDL-cholesterol at 1 year [mg/dl] LDL-cholesterol at 1 year [mg/dl] Triglyceride at 1 year [mg/dl] Baseline GFR [ml/min/1.73m 2 ] * HR to the control category shown left to the slash, or HR per unit. Ueki K, Sasako T, Nangaku M, Kadowaki T: Unpublished results 31

32 Components of Renal Events All Events Conventional Intensive Normo- to micro- or macroalbuminuria Micro- to macroalbuminuria Doubling of serum creatinine End-stage renal failure 5 0 Ueki K, Sasako T, Nangaku M, Kadowaki T: Unpublished results 32

33 Summary of Renal Events in J-DOIT3 1. Cumulative incidence of renal events mainly composed of normo- to micro- or macroalbuminuria was significantly (p<0.001) reduced by 32% in intensive therapy group. 2. Cox regression analysis on the renal events according to variables at 1 year after randomization revealed that 1% increase in HbA1c was associated with 20% increase in the renal events. 3. Cox regression analysis on egfr decline (baseline egfr <60) according to variables at 1 year after randomization revealed that higher systolic blood pressure was associated with faster egfr decline. 4. Only 5 end-stage renal failure occurred in conventional therapy group and no end-stage renal failure occurred in intensive therapy group. 33

34 Cumulative glucose lowering effects(δhba1c x intervention years)and reduction of cardiovascular events(3-point MACE) 3-point MACE HR DIGAMI2 ELIXA SAVOR TECOS ALEGARDIO ORIGIN RECORD BARI2D ADVANCE ACCORD EMPA-REG SUSTAIN 6 LOOK AHEAD VADT UKPDS 0.7 EXAMINE LEADER PROACTIVE 0.6 KUMAMOTO 0.5 Steno J-DOIT Diabetes Obes Metab 2018; 20(2): ΔHbA1c x years 34

35 Incidence of CV events in RCTs mainly on primary prevention All-cause death [/1000 person-years] Conventional : Con, Intensive : Int Cardiovascular death / all-cause death [%] Myocardial infarction [/1000 person-years] Stroke [/1000 person-years] Con Con Con Int UKPDSJDCS J-DOIT3 NA Con Con Con Int UKPDSJDCS J-DOIT Con Con Con Int UKPDSJDCS J-DOIT3 0 Con Con Con Int UKPDSJDCS J-DOIT3 UKPDS :Registration (yr) , Duration of study 10yrs JDCS :Registration (yr) , Duration of study 7.9yrs J-DOIT3:Registration (yr) , Duration of study 8.5yrs 35

36 J-DOIT3 Follow-Up Study Subjects Facilities Duration of follow-up Primary Outcome Secondary Outcome Exploratory Outcomes Measures Treatment Targets 1,746 out of 2,253 cases who completed J-DOIT3 (Intervention) agreed to participate and have been registered 76 out of 81 institutions which participated in J-DOIT3 (Intervention) 5 years (yearly survey) Either of death, myocardial infarction, stroke, coronary revascularization or cerebral revascularization (composite) All-cause death; either of death, myocardial infarction, stroke; onset or progression of nephropathy; lower limb vascular events; onset or progression of retinopathy Severe hypoglycemia, hospitalization due to heart failure, malignant neoplasms, fracture, cognitive function, QOL Occurrence of death or macrovascular event, urinary albumin, fundus examination, body height, body weight, waist circumference, plasma glucose/hba1c, blood pressure, lipids, smoking, drinking, medications Flexibly set by each participant and the physician in charge 36

37 Conclusion - A multifactorial intervention with stricter targets than those recommended by current guidelines significantly reduced the cerebrovascular events in patients with type 2 diabetes, even as compared with the current standard care. - The stricter multifactorial intervention significantly decreased the renal event and the eye event risk in patients with type 2 diabetes. - A follow-up observational study is currently evaluating legacy effects on cardiovascular events, renal events, cognitive function, ADL, healthy longevity and longevity. 37

38 Significance and translation of J-DOIT3 Before J-DOIT3 After J-DOIT3 Intensive intervention on lifestyle and integrated treatment for risk factors Vascular complications in the diabetic patients Prevention of vascular complications っ強力な Healthy life expectancy QOL of patient Medical expenses J-DOIT3 provides the first evidence in the treatment of diabetes that stricter multifactorial intervention further suppressed stroke and kidney disease in T2 DM Healthy life expectancy QOL of patient Medical care cost 38

39 Take Home Message 1. Asians are prone to develop type 2 diabetes at a lower BMI than Caucasians. 2. Asian-specific T2D genes are begun to be identified such as genes implicated in insulin secretion and incretin pathways. 3. Multifactorial intervention stricter than the current standard care significantly further reduced stroke and renal diseases in type 2 diabetes