How evidence-based medicine has informed the management of ...

How evidence-based medicine has informed the management of ...

Module 1 - Type 2 Diabetes: the principles of its pathogenesis, progression and management Screening detection and prevention UN Resolution 21st December 2006 A call to action for all UN member states to develop national policies for the prevention, treatment and cure of diabetes. The significance is monumental. Professor Martin Silink IDF President and Chair The Unite for Diabetes Campaign Primary Endocrinopathies: Treating a Moving Target Insulin Resistance Ins u li nA cti Type 2 Diabetes b-cell Dysfunction Hy

on ly g r pe a mi e c Insulin Concentration Insulin Resistance Liver muscle fat Euglycaemia Normal Pancreatic b-cell Failure IGT Obesity Diagnosis Of T2DM Progression of T2DM mass Beta cell function (%) 100 80 60

10-12 Year Probationary Period 40 Clinical Diagnosis 20 0 12 10 8 6 4 2 0 2 Years from diagnosis of diabetes 4 6 Adapted from UKPDS 16. Diabetes 1995; 44: 1249-58 IGT is driving the worldwide diabetes pandemic % of population 50 40

IGT 30 20 Undiagnosed type 2 diabetes 10 Diagnosed type 2 diabetes 0 20-44 45-54 55-64 65 Age (years) Harris MI et al. Consultant 1997;37 Suppl:S9 Diagnostic criteria for IGT and IFG Plasma Glucose (mmol/L) >11.1 11 IGT

8 Diabetes FPG >7 Normal FPG <6.1 Diabetes <7.8 Normal IFG -30 0 Fasting OGTT 30 60 90 120 150 180 Minutes mmol/L mg/dL 6.1 110

7.0 126 7.8 140 11.1 200 Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Diabetes Care. 1997;20:1183-97 Progression to type 2 diabetes Annual rates of progression to more severe forms of glucose intolerance IFG IGT IFG + IGT Type 2 diabetes 1.3 3.9 0.5 0.6

IFG - 3.7 6.5 2.4 IGT - - 0.9 2.7 IFG + IGT - - - 9.9 Normal glucose tolerance Koehler et al. Diabetologia 2001;44 Suppl 1:A108

PATHWAYS TO IGT Sedentary lifestyle Diet Genes Intra-uterine malnutrition Obesity Insulin resistance / hyperinsulinaemia Major causative pathways Secondary consequences of hyperglycaemia Beta cell defect IGT 10 8 6 4 2 Total no. with IGT 12

0 < 20 20 22 -22 .5 .4 -2 25 4.9 -2 27 6.9 -2 30 9.9 -3 4. 9 >3 5 < 20 20 22 -22 .5 .4 -2 25 4.9 -2 27 6.9 -2 30 9.9 -3 4. 9 >3 5 (%) IGT

Obesity and prevalence of IGT 14 300 200 100 0 Body mass index (kg/m2) Lindahl et al. Diabetes Care 1999;22:1988-92 What are the benefits of prevention ? Progression to diabetes leads to the need for intervention measures with limited success. Diabetes is irreversible Patients with diabetes develop complications of the eye, kidneys and nerves Prevention is Superior to Treatment Patients have excess risk of strokes, heart attacks and premature death Pratley RE. Br J Diabetes Vasc Dis 2007; 7: 120-129 Survival (9-Year Follow-up): Hoorn Study (WHO Criteria) Fraction of cumulative survival of subjects 1.0

Normal glucose tolerance (NGT) Impaired glucose tolerance (IGT) 0.9 0.8 Newly-diagnosed DM 0.7 0.6 0.5 Known DM 0 2 4 6 8 10 Follow-up (years) De Vegt et al. Diabetes Care 2000;23:404 Subjects at High Risk of Type 2 Diabetes Subjects in the transistional state of glucose intolerance First degree relatives of type 2 diabetics.

Overweight and obese subjects. Subjects developing gestational diabetes. Some ethnic groups Diabetes UK criteria for screening a) White people aged over 40 years and people from Black, Asian and minority ethnic groups aged over 25 with one or more of the risk factors below: - a first degree family history of diabetes and/or who are overweight/obese/morbidly obese with a BMI of 25-30 kg/m2 and above(8,9), and who have a sedentary lifestyle - Waist measurement of over > 94cm (> 37 inches) for White and Black men and > 80cm (> 31.5 inches) for White, Black and Asian women, and > 90cm (> 35 inches) for Asian men. b) People who have ischaemic heart disease, CVD, PVD or treated hypertension c) Women who have had gestational diabetes who have tested normal following delivery (screen within 6 weeks of delivery, then 1 and 3 years d) Women with polycystic ovary syndrome who have a BMI > 30 e) People who are known to have impaired glucose tolerance or impaired fasting glycaemia. f) People who have severe mental health problems. g) People who have hypertriglyceridemia not due to alcohol excess or renal disease. Risk Assessment Questionnaires (United States, Canada and UK) Risk Assessment Diabetes UK ADA CDA Age

YES YES YES Gender YES YES YES Ethnicity YES YES YES Relatives with diabetes YES YES YES Waist circumference YES NO

YES BMI YES YES YES High blood pressure YES YES YES Physical activity NO YES YES Vegetable /fruit eater YES History of raised BG YES Level of Education

YES General Health YES Smoking YES Screening Questionnaire based on risk ( Public Health Agency of Canada 2009 ) Screening Questionnaire based on risk ( Public Health Agency of Canada 2009 ) O T N I U O Y ES S I R O G K E S T I A R

C H E G I D I H U r G o E G T N I A R R DE SCO O M , D E S A E R C N I , LOW

NATURAL HISTORY OF IGT Normal 33% IGT After 10 years 33% 33% IGT Diabetes IGT: A Moving Target 10 Years Follow-Up IGT Diabetes IGT NGT Are subjects who regress to NGT at excess risk of diabetes in the future, and what is their cardiovascular risk? Do they still need monitoring and treatment? Who should take the responsibility for prevention policies ? Public Health Authorities, Medical Associations Diabetes Organisations ADA

IDF Nathan. Diabetes Care 2007; 30: 753-759 Preventing diabetes: How can we? Lifestyle or drugs? How can we identify those at greatest risk Is prevention possible in real life? Is prevention cost-effective? Alberti. Diabet Med 2007; 24: 451-463 Diabetes Prevention Trials: Lifestyle and Oral Antidiabetic Agents Trial Treatment Relative Risk Finnish Diabetes Intensive lifestyle vs Control Da Qing Study Intensive lifestyle vs Control Diabetes Preven- Intensive lifestyle vs Placebo 58% tion Program (DPP)

Metformin vs Placebo 31% STOP-NIDDM Acarbose vs. Placebo 21% CANOE Rosiglitazone + Metformin vs Placebo Dream Rosiglitazone Navigator Nateglinide vs Placebo 58% 38% 66% 39% 7% Study Interventions IFG 5.3-6.9 IGT 7.8-11.0 Eligible participants

Randomized Standard lifestyle recommendations MEAN AGE = 51y BMI =34 Intensive Lifestyle (n = 1079) Metformin Placebo 850mg bd (n = 1073) (n = 1082) Diabetes Prevention Programme Cumulative diabetes incidence (%) 40 MEDIAN FOLLOW-UP = 2.8 YEARS Placebo 30 Metformin RR 31%

RR 58% Lifestyle 20 Treatment 10 0 0 0.5 1.0 1.5 2.0 2.5 Incidence of diabetes per 100 person years NNT Placebo 11.0 Metformin 7.8

13.9 3.0Lifestyle 3.5 4.0 4.8 6.9 Years in Study N Engl J Med 2002; 346: 393-403 Subgroup Analyses in the Diabetes Prevention Program Reduction in diabetes risk versus placebo (%) Age (y) 25 4 4 59 60 > 45 FPG (mmol/L) .1 6 .0 7 <

6.1 5.3 Intensive lifestyle intervention BMI (kg/m2) 30 <35 35 < > 22 30 Metformin N Engl J Med 2002; 346: 393-403 Prevention Of Type 2 Diabetes: Barriers To Lifestyle Interventions Exercise is not an option for everyone: particularly disabled elderly subjects increased risk of sports injuries. Diet is not always on option either Economic Availability etc (DPPOS) Interventions in open label study include : Lifestyle and Metformin 850mg bd Designed to measure Incidence of diabetes study ( DPP) lasting 2.8 years but then extended to complications outcomes (DPPOS) lasting 10years plus

DPP Research Group Lancet 2009; 374: 1654-1663 DPP+DPPOS Incidence of Diabetes at 10years 10 year frequency of Type 2 diabetes Placebo 52% Metformin 47% Lifestyle 42% o eb c Pla n mi r tfo le e y t M es Lif DPPOS (7.8Y)

Cases of T2DM 100 person years Placebo 5.9 Metformin 4.9 Lifestyle 5.6 Lancet 2009; 374:1654-63 Effect of Interventions on Weight DPP+DPPOS 16% RR of diabetes per kg weight loss YEARS 0 1 2 3 4 5 6

7 8 9 10 DPP Research Group Lancet 2009; 374: 1654-1663 Diabetes cumulative incidence rates Effect of regression to normal glucose regulation on risk of progressing to diabetes NEVER REACHED NORMAL GLUCOSE REGULATION IN DPP 56% Normalising glucose regulation even transiently in high risk subjects reduces onset of T2DM REACHED (AT LEAST ONCE) NORMAL GLUCOSE REGULATION IN DPP YEARS in DPPOS follow-up DPP Research Group Lancet 2012; 379: 2243-2251 Effect of regression to normal glucose regulation on risk of progressing to diabetes [Stratified by treatment group in DPP] LIFESTYLE NEVER REACHED NORMAL GLUCOSE REGULATION IN DPP

METFORMIN PLACEBO Subjects on lifestyle intervention with intractible IFG/IGT are at greatest risk of developing T2DM. Think about additional treatment REACHED (metformin?) (AT LEAST ONCE) NORMAL GLUCOSE REGULATION IN DPP DPP Research Group Lancet 2012; 379: 2243-2251 Prevention with Low dose Combination therapy Metformin plus Rosiglitazone Outcome Met 1000mg Rosi 4mg Placebo Diabetic 15.9% 79.6% 4.6% 41.8% 53.1% 5.1% Median FU 3.9 y NGT

IFG/IGT 66% RRR 95% CI 41-80 Entry = IGT+IFG +Risk Factor Zinman B et al. Lancet 2010 ; 376: 103-111 Prevention in High Risk Geographic Regions Chinese (Wenying) Relative risk reduction (%) Relative risk reduction (%) Asians (IDPP) p=0.018 p=0.029 p=0.022 p=0.0928 p=0.0002 p=0.0001 Ramachandran. Diabetologia 2006; 49: 289-97 Wenying. Chinese J Endocrinol & Metab 2001; 17: 131-4 NAVIGATOR Trial in IGT subjects educe r

ia m e a c ly andial g r p t s o p g n i CV m o r f t c e t Can lower o r s an d p e t e b ia d f

o onset tid , ns ? o g i t m a 0 ic 6 l p e d m i o n c ategli n h t i w n g i s ial de vartis. o N

m 2x2 factor o r f n a valsart d n a o b e c a pl P s t ud y P D = e g n a dent style ch i e c f in li ( e s

v r i a s e n y e Int d for 5 e w o ll o f ) T risk (IG h g i h comes) t 6 u 0 o 3 9 V C (

s r 6.5 yea d n a ) s e t e iabetes d diab f o k is r e h ucing t d e r n i t fi e n be t CV s o n

in a g a E g D I n i t IN protec NATEGL n i t fi e n e b o E -- n NATEGLINID s complication Navigator Study Group N Engl J Med 2010; 362: 1463-76 DPP Outcomes for Subjects with the Metabolic Syndrome* Cumulative incidence of the metabolic syndrome * NCEP ATP III

Placebo * 17%a 41%b Metformin Lifestyle N=490 N=503 N=530 Time since randomization, years a p=0.03 b p<0.001 Orchard. Ann Intern Med 2005; 142: 611-9 Definition of the Metabolic Syndrome ( IDF/AHA/NHLBI/WHO ) 2009 Elevated waist circumference (Sub-Sahara M/F 94/8 Raised TG: 150 mg/dl (1.7 mmol/l) Reduced HDL: 40 mg (1.03 mmol/l) males 50 mg (1.29 mmol/l) females Raised BP

130 (systolic) or 85 diastolic mm Raised FPG 100 mg (5.6 mmol/l) or previous diagnosis type 2 DM Presence of three out of five risk factors = metabolic syndrome Joint Scientific Statement on Metabolic syndrome, IDF/AHA/ WHO/NHLBI. Alberti et al, Circulation 2009 : 120 : 1640-1645 Cumulative incidence (%) DPP Outcomes for Subjects with past history of GDM 50 Risk reduction vs placebo 51% by metformin (p=0.006) 55% by lifestyle (p=0.002) 45 40 35 30 PLACEBO No=122 Risk reduction vs metformin 8% by lifestyle (p=0.781) NS 25 METFORMIN No=110

20 15 10 LIFESTYLE 5 No=117 0 0 0.5 1 1.5 2 2.5 3 Years from randomization Ratner RE et al. J Clin Endocrinol Metab 2008; 93: 4774-9 Cost Effectiveness of DPP interventions in adherent* participants *5% weight loss (L) Taking (Met) at 80% of clinic visits Intervention Group LIFESTYLE Intervention

Medical Costs $4810 METFORMIN 49.4% RRR $2934 20.8% RRR PLACEBO $768 DPP Research group ,Herman WH. Am J Manag Care 2013;19:194-202 Cost Effectiveness of DPP interventions in adherent* participants *5% weight loss (L) Taking (Met) at 80% of clinic visits Intervention Group LIFESTYLE METFORMIN 49.4% RRR Intervention Medical Costs Non- Intervention Medical cost

$4810 $4250 < Placebo $2934 $3251 < Placebo $768 ---- 20.8% RRR PLACEBO Conclusion : Lifestyle and metformin interventions are cost saving versus placebo DPP Research group ,Herman WH. Am J Manag Care 2013;19:194-202 Conclusions from Intervention Trials Lifestyle , if intensive, produces the best outcomes Lifestyle , watch out for weight gain with time Lifestyle unresponsive subjects add pcological therapy Lifestyle plus pcological therapy additive check ethnicity Small dose of combined pcological therapy worth trying Lifestyle , also metformin has benefits in MS and GDM Pcological therapy can be most cost effective RESERVES Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial Ramipril 515

Placebo mg (n=2646) (n=2623) Rosiglitazone 48 mg (n=2635) Rosiglitazone Rosiglitazone + ramipril + placebo Placebo (n=2634) Ramipril + placebo Placebo + placebo Key inclusion criteria: Impaired fasting glucose (FPG 6.16.9 mmol/L) and/or impaired glucose tolerance (FPG <7.0 mmol/L and 2 h OGTT 7.811.0 mmol/L No prior diabetes (except gestational diabetes) No prior cardiovascular disease DREAM Investigators Lancet 2006;368:1096-105 DREAM Investigators. NEJM 2006;355:1551-62 Main results of the DREAM trial Diabetes or deatha p<0.0001 p<0.0001 p=0.001

p=0.15 Favours drug Favours drug 0.2 0.4 0.6 0.8 1.0 1.2 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Hazard ratio (95% CI) Hazard ratio (95% CI) Rosiglitazone vs. placebo a Primary endpoint Reversion to normoglycaemia Ramipril vs. placebo DREAM Investigators. Lancet 2006;368:1096-105 DREAM Investigators. NEJM 2006;355:1551-62 Tolerability/safety outcomes in the rosiglitazone arm of DREAM Rosiglitazo ne (n=2635) Placebo (n=2634

) Withdrew for weight gain (%)a 1.9 0.6 Withdrew for oedema (%) 4.8 1.8 Confirmed heart b 0.5 0.1 Net mean weight gain of 2.2 kg in the rosiglitazone group vs. placebo. failure (%) a

p=0.01 vs. placebo. b DREAM Investigators. Lancet 2006;368:1096-105 STOP-NIDDM: Time To Any CVD Event (First Event Only) Survival distribution function Mean treatment duration 1.00 0.99 0.98 Acarbose 0.97 0.96 Placebo 0.95 0.94 p = 0.0326 0.93 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

Days after Randomization Chiasson et al. Diabetologia 2002; 45, Suppl. 2: A104 Diabetes and cardiovascular outcomes in the STOP-NIDDM trial Diabetes (p=0.0015) MI (p=0.02) Revascularisation (p=0.18) CV death (p=0.63) CVE (p=0.51) 6.11 3.07 18.30 PVD (p=0.93) Any CV event (p=0.51) 0.0 0.2 0.4 0.6 0.8 1.0 1.2 Hazard ratio (95% CI)

1.4 1.6 erebrovascular event or stroke; PVD: peripheral vascular disease. Chiasson JL et al. Lancet 2002;359:2072-7; Chiasson JL et al. JAMA 2003;290 Gastrointestinal tolerability of acarbose in STOP-NIDDM Any GI event Flatulence Diarrhoea Abdominal pain Dyspepsia Nausea Acarbose (n=714) Placebo (n=715) Constipation Gastroenteritis Withdrew for GI event 0 20 40 60 80 % 100 Chiasson JL et al. Lancet 2002;359:2072

Preventing Diabetes: TRIPOD Study People with Diabetes 53% Placebo RR=0.44 12.3%/yr 19% Troglitazo 5.4%/yr ne Months on Study Other diabetes prevention studies in subjects with impaired glucose tolerance (IGT) Study N Evaluations Diabetes risk reductionsa DaQing study (China)1 577 Diet Exercise

Diet + exercise XENDOS2 694b 31% 46% 42% 45% Orlistatc vs. control or placebo; bsub-group with IGT; c combined with intensive lifestyle 1. Pan X et al. Diabetes Care 1997;20:537-44 intervention a 2. Torgerson JS et al. Diabetes Care 2004;27:15561 Xendos Trial: Cumulative Incidence Type 2 Diabetes Incidence Placebo + lifestyle of T2D (%) Xenical + lifestyle 10

9.0% 8 RR^ 37% p=0.0032 6.2% 6 4 ^Hazard ratio reduction vs placebo plus lifestyle 2 0 0 26 52 78 Sjostrom et al. 9th ICO, Sao Paulo 2002 104 Week 130

156 182 208 Multivariate-adjusted hazard ratios for the incidence of type 2 diabetes by volume of coffee consumption among men & women combined Coffee consumption <=2 cups 3-4 cups 5-6 cups 7-9 cups >=10 cups P for trend Age and exam year adjusted 1.00 0.79 (0.59 -1.04) 0.67 (0.50 -0.88) 0.66 (0.46 -0.96) 0.53 (0.33 -0.85) 0.016 Multivariate adjusted 1.00 0.77 (0.57 -1.03) 0.56 (0.41 -0.75) 0.56 (0.38 -0.83) 0.39 (0.24 -0.65) <0.001

Adjusted for age, sex, exam year, BMI, SBP, smoking, education, physical activity, alcohol and tea consumption

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