Module 1 - Type 2 Diabetes: the principles of its pathogenesis, progression and management Screening detection and prevention

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 UN Resolution 21 st December 2006

Primary Endocrinopathies: Treating a Moving Target Insulin Resistance Type 2 Diabetes b-cell Dysfunction Hyperglycemia Euglycaemia Insulin Concentration Pancreatic b-cell Failure Insulin Resistance Liver muscle fat Insulin Action Normal IGT ± Obesity Diagnosis Of T2DMProgression of T2DM

Loss of Beta cell function and mass Adapted from UKPDS 16. Diabetes 1995; 44: Years from diagnosis of diabetes Beta cell function (%) –10–8–6–4–20246 – Year Probationary Period Clinical Diagnosis

Harris MI et al. Consultant 1997;37 Suppl:S9 IGT Undiagnosed type 2 diabetes Diagnosed type 2 diabetes  65 Age (years) % of population IGT is driving the worldwide diabetes pandemic

Diagnostic criteria for IGT and IFG IFG Minutes Fasting Plasma Glucose (mmol/L) 8 11 IGT Diabetes FPG >7 Normal FPG <6.1 Diabetes >11.1 Normal <7.8 OGTT Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Diabetes Care. 1997;20: mmol/Lmg/dL

IFGIGTIFG + IGT Type 2 diabetes Normal glucose tolerance IFG IGT IFG + IGT Progression to type 2 diabetes Annual rates of progression to more severe forms of glucose intolerance Koehler et al. Diabetologia 2001;44 Suppl 1:A108

PATHWAYS TO IGT Insulin resistance / hyperinsulinaemia Intra-uterine malnutrition Genes Sedentary lifestyle Diet Obesity Beta cell defect IGT Major causative pathways Secondary consequences of hyperglycaemia

Obesity and prevalence of IGT Lindahl et al. Diabetes Care 1999;22: Body mass index (kg/m 2 ) < >35 (%) IGT < >35 Total no. with IGT

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 Patients have excess risk of strokes, heart attacks and premature death What are the benefits of prevention ? Prevention is Superior to Treatment Pratley RE. Br J Diabetes Vasc Dis 2007; 7:

Survival (9-Year Follow-up): Hoorn Study (WHO Criteria) De Vegt et al. Diabetes Care 2000;23:40– Follow-up (years) Fraction of cumulative survival of subjects Normal glucose tolerance (NGT) Impaired glucose tolerance (IGT) Newly-diagnosed DM Known DM

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

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 kg/m 2 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. Diabetes UK –criteria for screening

Risk AssessmentDiabetes UK ADACDA AgeYES GenderYES EthnicityYES Relatives with diabetesYES Waist circumferenceYESNOYES BMIYES High blood pressureYES Physical activityNOYES Vegetable /fruit eaterYES History of raised BGYES Level of EducationYES General HealthYES SmokingYES Risk Assessment Questionnaires (United States, Canada and UK)

Screening Questionnaire based on risk ( Public Health Agency of Canada 2009 )

Screening Questionnaire based on risk ( Public Health Agency of Canada 2009 ) SCORING GUIDE CATEGORISES YOU INTO LOW, INCREASED, MODERATE or HIGH RISK

NATURAL HISTORY OF IGT After 10 years 33% 33% 33% Normal Diabetes IGT IGT

IGT Diabetes IGT NGT IGT: A Moving Target 10 Years Follow-Up 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 ? Nathan. Diabetes Care 2007; 30: Alberti. Diabet Med 2007; 24: ADA IDF 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? Public Health Authorities, Medical Associations Diabetes Organisations

ADA Treatment Recommendations Nathan. Diabetes Care 2007; 30 (3): IFG or IGT Individuals with IFG and IGT and any of the following: <60 years of age BMI >35 kg/m2 Family history of diabetes in first-degree relatives Elevated triglycerides Reduced HDL cholesterol Hypertension A1C >6.0% Treatment Recommendations Lifestyle modification (i.e. 5-10% weight loss and moderate intensity physical activity ~30 min/day) Lifestyle modification (as above) and/or metformin 850mg twice a day

Diabetes Prevention Trials: Lifestyle and Oral Antidiabetic Agents TrialTreatmentRelative Risk Finnish Diabetes Intensive lifestyle vs Control  58% Da Qing Study Intensive lifestyle vs Control  38% Diabetes Preven-Intensive lifestyle vs Placebo  58% tion Program (DPP)Metformin vs Placebo  31% STOP-NIDDMAcarbose vs. Placebo  21% CANOERosiglitazone + Metformin vs Placebo 66% Dream Rosiglitazone Navigator Nateglinide vs Placebo 7% 39%

Study Interventions Eligible participants Randomized Standard lifestyle recommendations Intensive Metformin Placebo Lifestyle 850mg bd (n = 1079) (n = 1073) (n = 1082) MEAN AGE = 51y BMI =34 IFG IGT

Cumulative diabetes incidence (%) Years in Study RR  58% Placebo Metformin Lifestyle RR  31% N Engl J Med 2002; 346: Diabetes Prevention Programme MEDIAN FOLLOW-UP = 2.8 YEARS TreatmentIncidence of diabetes per 100 person years NNT Placebo11.0 Metformin Lifestyle4.86.9

Reduction in diabetes risk versus placebo (%) Intensive lifestyle interventionMetformin Age (y) 25–44 45–59 >60 FPG (mmol/L) 5.3–< –7.0 BMI (kg/m 2 ) 22–<3030–<35 >35 Subgroup Analyses in the Diabetes Prevention Program N Engl J Med 2002; 346:

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 Prevention Of Type 2 Diabetes: Barriers To Lifestyle Interventions

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: (DPPOS)

DPP+DPPOS Incidence of Diabetes at 10years Lancet 2009; 374: year frequency of Type 2 diabetes Placebo52% Metformin47% Lifestyle42% Placebo Metformin Lifestyle DPPOS (7.8Y) Cases of T2DM 100 person years Placebo5.9 Metformin4.9 Lifestyle5.6

Effect of Interventions on Weight YEARS DPP+DPPOS DPP Research Group Lancet 2009; 374: % RR of diabetes per kg weight loss

DPP Research Group Lancet 2012; 379: NEVER REACHED NORMAL GLUCOSE REGULATION IN DPP REACHED (AT LEAST ONCE) NORMAL GLUCOSE REGULATION IN DPP YEARS in DPPOS follow-up Diabetes cumulative incidence rates 56% Effect of regression to normal glucose regulation on risk of progressing to diabetes Normalising glucose regulation even transiently in high risk subjects reduces onset of T2DM

DPP Research Group Lancet 2012; 379: NEVER REACHED NORMAL GLUCOSE REGULATION IN DPP REACHED (AT LEAST ONCE) NORMAL GLUCOSE REGULATION IN DPP LIFESTYLE METFORMIN PLACEBO Effect of regression to normal glucose regulation on risk of progressing to diabetes [Stratified by treatment group in DPP] Subjects on lifestyle intervention with intractible IFG/IGT are at greatest risk of developing T2DM. Think about additional treatment (metformin?)

Prevention with Low dose Combination therapy – Metformin plus Rosiglitazone Entry = IGT+IFG +Risk Factor Zinman B et al. Lancet 2010 ; 376: Outcome Median FU 3.9 y Met 1000mg Rosi 4mg Placebo Diabetic 15.9%41.8% NGT 79.6%53.1% IFG/IGT 4.6% 5.1% 66% RRR 95% CI 41-80

CANOE trial –Outcome results median follow-up 3.9 years Time to occurrence of T2DM Glycaemic status Placebo Met +Rosi 66% RRR 95%CI Placebo Met+Rosi Zinman B et al. Lancet 2010 ; 376: No clinically relevant adverse events

Relative risk reduction (%) p=0.018p=0.029p=0.022 Prevention in High Risk Geographic Regions Ramachandran. Diabetologia 2006; 49: Wenying. Chinese J Endocrinol & Metab 2001; 17: Relative risk reduction (%) p= p= p= Asians (IDPP) Chinese (Wenying)

NAVIGATOR Trial in IGT subjects Navigator Study Group N Engl J Med 2010; 362: Can lowering postprandial glycaemia reduce onset of diabetes and protect from CV complications ? 2x2 factorial design with nateglinide 60mg tid, placebo and valsartan from Novartis. Intensive lifestyle change = DPP study 9306 high risk (IGT) followed for 5 years (incident diabetes) and 6.5 years (CV outcomes) NATEGLINIDE -- no benefit in reducing the risk of diabetes NATEGLINIDE -- no benefit in protecting against CV complications

DPP Outcomes for Subjects with the Metabolic Syndrome* Orchard. Ann Intern Med 2005; 142: * NCEP ATP III N=490 N=503 N=530 Placebo Metformin Lifestyle * 17% a 41% b Time since randomization, years Cumulative incidence of the metabolic syndrome a p=0.03 b p<0.001

Definition of the Metabolic Syndrome ( IDF/AHA/NHLBI/WHO ) 2009 Elevated waist circumference (Sub-Sahara M/F 94/80cm) 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 mmHg 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 :

DPP Outcomes for Subjects with past history of GDM PLACEBO No=122 METFORMIN No=110 LIFESTYLE No=117 Years from randomization Cumulative incidence (%) Ratner RE et al. J Clin Endocrinol Metab 2008; 93: Risk reduction vs placebo 51% by metformin (p=0.006) 55% by lifestyle (p=0.002) Risk reduction vs metformin 8% by lifestyle (p=0.781) NS

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

Intervention Group Intervention Medical Costs Non- Intervention Medical cost LIFESTYLE$4810 $4250 < Placebo METFORMIN$2934 $3251 < Placebo PLACEBO$ Conclusion : Lifestyle and metformin interventions are cost saving versus placebo DPP Research group,Herman WH. Am J Manag Care 2013;19: Cost Effectiveness of DPP interventions in adherent* participants *5% weight loss (L) Taking (Met) at 80% of clinic visits 49.4% RRR 20.8% RRR

Lifestyle, if intensive, produces the best outcomes Lifestyle unresponsive subjects – add p’cological therapy Lifestyle, watch out for weight gain with time Small dose of combined p’cological therapy worth trying Lifestyle plus p’cological therapy additive – check ethnicity Lifestyle, also metformin has benefits in MS and GDM Conclusions from Intervention Trials P’cological therapy can be most cost effective

RESERVES

Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial Ramipril 5–15 mg (n=2623) Placebo (n=2646) Rosiglitazone 4–8 mg (n=2635) Rosiglitazone + ramipril Rosiglitazone + placebo Placebo (n=2634) Ramipril + placeboPlacebo + placebo Key inclusion criteria: Impaired fasting glucose (FPG 6.1–6.9 mmol/L) and/or impaired glucose tolerance (FPG <7.0 mmol/L and 2 h OGTT 7.8–11.0 mmol/L No prior diabetes (except gestational diabetes) No prior cardiovascular disease DREAM Investigators Lancet 2006;368: DREAM Investigators. NEJM 2006;355:

Main results of the DREAM trial DREAM Investigators. Lancet 2006;368: DREAM Investigators. NEJM 2006;355: Rosiglitazone vs. placeboRamipril vs. placebo Hazard ratio (95% CI) Diabetes or death a Reversion to normoglycaemia Favours drug p< p=0.15 p= a Primary endpoint

Tolerability/safety outcomes in the rosiglitazone arm of DREAM Rosiglitazone (n=2635) Placebo (n=2634) Withdrew for weight gain (%) a Withdrew for oedema (%) Confirmed heart failure (%)0.5 b 0.1 a Net mean weight gain of 2.2 kg in the rosiglitazone group vs. placebo. b p=0.01 vs. placebo. DREAM Investigators. Lancet 2006;368:

STOP-NIDDM: Time To Any CVD Event (First Event Only) (First Event Only) Days after Randomization Survival distribution function Mean treatment duration Acarbose Placebo p = 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) CVE (p=0.51) Any CV event (p=0.51) CV death (p=0.63) PVD (p=0.93) Hazard ratio (95% CI) CVE: cerebrovascular event or stroke; PVD: peripheral vascular disease. Chiasson JL et al. Lancet 2002;359:2072-7; Chiasson JL et al. JAMA 2003;290:486-94

Gastrointestinal tolerability of acarbose in STOP-NIDDM Withdrew for GI event Gastroenteritis Constipation Nausea Dyspepsia Abdominal pain Diarrhoea Flatulence Any GI event Acarbose (n=714) Placebo (n=715) % Chiasson JL et al. Lancet 2002;359:2072-7

Preventing Diabetes: TRIPOD” Study Months on Study People with Diabetes 53% 19% RR=0.44 Placebo 12.3%/yr Troglitazone 5.4%/yr

Other diabetes prevention studies in subjects with impaired glucose tolerance (IGT) Study DaQing study (China) 1 XENDOS 2 Evaluations Diet Exercise Diet + exercise Orlistat c Diabetes risk reductions a – 31% – 46% – 42% – 45% N b a vs. control or placebo; b sub-group with IGT; c combined with intensive lifestyle intervention 1. Pan X et al. Diabetes Care 1997;20: Torgerson JS et al. Diabetes Care 2004;27:155–61

Xendos Trial: Cumulative Incidence Type 2 Diabetes Sjostrom et al. 9th ICO, Sao Paulo 2002 Incidence of T2D (%) p= Week 9.0% 6.2% RR^ 37% ^Hazard ratio reduction vs placebo plus lifestyle Placebo + lifestyleXenical + lifestyle

Multivariate-adjusted hazard ratios for the incidence of type 2 diabetes by volume of coffee consumption among men & women combined Adjusted for age, sex, exam year, BMI, SBP, smoking, education, physical activity, alcohol and tea consumption Coffee consumption Age and exam year adjusted Multivariate adjusted <=2 cups cups 0.79 ( ) 0.77 ( ) 5-6 cups 0.67 ( ) 0.56 ( ) 7-9 cups 0.66 ( ) 0.56 ( ) >=10 cups 0.53 ( ) 0.39 ( ) P for trend <0.001