Type 2 Diabetes Screening detection and prevention Dr. Ghanei Endocrinologist

Affects % of all cases of diabetes. Age – extremely variable but becoming commoner in children. Triggered by environmental and genetic factors. Type 2 diabetes is a progressive disease with complex aetiology Treated with exercise, diet, oral regimens and injectables –GLP-1 therapy and insulin but condition is best described as insulin requiring rather than insulin dependent. Affects % of all cases of diabetes. Age – extremely variable but becoming commoner in children. Triggered by environmental and genetic factors. Two endocrine defects: insulin resistance and failure of the beta cell. Progressive deterioration Not a mild disease – tissue damage affecting microvasculature – eyes, kidneys and nerves. Long-term risk of life threatening premature macrovascular complications – heart attacks, stroke, leg amputation, early death.

Emerging Risk Factor Collaboration N Engl J Med 2011; 364: Deaths Diabetics vs Non Diabetics All Causes Cancer Non-vascular Vascular 97 cohort studies, 125 million person-years, 820,900 subjects, 123,205 deaths

Life lost due to Diabetes Emerging Risk Factor Collaboration N Engl J Med 2011; 364: A 50 year–old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 60% of the difference in survival attributable to vascular deaths and 40% excess to non-vascular/cancer deaths Deaths from unknown causes Non cancer non vascular Cancer deaths Vascular deaths

AfricaEuropeMid-East N. Africa South Central America North America Caribbean Western Pacific Percentage of All-Cause Deaths Attributed to Diabetes. Diabetes is a Leading Cause of Death Worldwide World IDF Diabetes Atlas, 5th edition, IDF 2011: 8.2%

High Rate of Complications at Diagnosis 50% of patients had tissue damage at enrolment 21%Retinopathy ( > 1 microaneurysm ) 18%Abnormal ECG 14%Two or more absent foot pulses 7%Impaired reflexes or diminished vibration sense 3%Angina pectoris 3%Intermittent claudication 2%Myocardial infarction 1%Stroke or TIA UKPDS 8. Diabetologia 1991; 34: UKPDS

Magnitude of the Problem The number of people with diabetes will nearly double within the first quarter of this millennium. World Health Report, 1997; Geneva: WHO.

(69%) (42%) (90%) (83%) (22%) (36%) (59%) IDF Diabetes Atlas, 5th edition, IDF 2011: IGT 2011 = 280 million 2030 = 398 million Increase 42% Diabetes 2011 = 366 million 2030 = 552 million Increase 51% Global Projections for the Diabetes Epidemic (millions) – 51% increase

Prevalence of T2DM* Adapted from NHANES III, Must A, et al. JAMA. 1999;282: Higher Prevalence of Type 2 Diabetes with increasing BMI: NHANES III

Developed Vs Developing Region Developed countries 6.2% 54.8 million 7.6% 72.2 million Developing countries 3.5% 99.6 million 4.9% million King et al, Diabetes Care 1998; 21:

Prevalence of Diabetes and IGT (MENA countries) Al-Maatouq M. Int J Clin Pract 2010; 64: in 10 subjects

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

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

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

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

What are the Drivers of the Epidemic for type 2 diabetes ? Obesity & diet Lack of exercise Urbanisation Aging Prosperity Ethnicity Family history (genetics)

Four seats for two customers !!!! Obesity

Factors associated with Type 2 diabetes Non Modifiable 1- Genetic factors. 2- Demographic determinants: such as age and ethnicity. Modifiable 1- Behavioral and lifestyle-related: such as obesity and physical inactivity. 2- Metabolic and intermediate risk categories: such as IGT, IFG and GDM.

Family History (Genetics) o Positive for type 2 diabetes - one parent - both parents - siblings - identical twin * Probability varies according to age at diagnosis 7% - 14% * 45% by age 65 7% - 14% * 58% - 75% American Diabetes Assoc Diabetes 2011 Vital Statistics

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

Prevalence of Diabetes and IGT (MENA countries) Al-Maatouq M. Int J Clin Pract 2010; 64: in 10 subjects

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

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

Why should we prevent diabetes? To reduce human suffering. To alleviate the economic burden. To prevent morbidity and mortality from diabetes-related CVD.

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:

Levels of prevention in Type 2 diabetes Primary: Includes activities aimed at preventing diabetes from occurring in susceptible populations or individuals. Secondary: Early diagnosis and effective control of diabetes in order to avoid or at least delay the progress of the disease. Tertiary: Includes measures taken to prevent complications and disabilities due to diabetes.

Preventive strategies: approaches in the design A population-based strategy, involving altering the lifestyle and environmental determinants of Type 2 diabetes. A high-risk strategy applying preventive measures on individuals identified as high-risk for Type 2 diabetes.

Primary prevention Most of the results on prevention come from studies on high risk groups rather than populations. Studies have shown that people with IGT has a 2-7 fold higher risk of progression to Type 2 diabetes than persons with normal glucose tolerance. Among the factors that predicted progression were obesity, elevated fasting and 2-h blood glucose and fasting insulin concentrations.

Types of interventions Behavioral interventions: including changing diet and increasing physical activity. And/or Pharmacological interventions: utilizing pharmaceutical agents to improve glucose tolerance and insulin sensitivity.

Behavioral interventions Several studies has shown that diet and physical activity reduced the incidence of Type 2 diabetes. Example: The Swedish Malmo study showed that diet and exercise for 5 years in men with IGT reduced the incidence of Type 2 diabetes by 50%. Eriksson et al, Diabetologia 1991; 34: 891-8

Finish Diabetes Prevention Study Risk of developing diabetes reduced by 58% after 4 years 11% vs 23% Cumulative risk of developing diabetes NNT = 8

Diabetes Prevention Programme (DPP) 27 centres 3234 participants > Or = 25 years BMI > or = 24 (22 for indo Asian) IGT –American Indian, African American, Hispanic American, Asia American, pacific islanders

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

DPP Average Age 51 Years BMI 34 Lifestyle intervention Weight reduction 7% Low fat diet Exercise for 150 mins per week OR metformin 850mgs BD

DPP Trial stopped 1 year early, after 2.8 yr of follow-up 29% Diabetes in controls 14% in Diet and exercise 22% in Metformin 3 year DataRisk Reduction 58% whole group 71% those aged >60yrs 31% Metformin (less effect in older and less obese)

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:

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?)

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

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

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

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

Effect of Acarbose on Reversion of IGT to NGT P< Placebo Acarbose Number of Patients n=241 (35.3%) n=212 (30.9%) IGT, impaired glucose tolerance; NGT, normal glucose tolerance. Chiasson JL, et al. Lancet. 2002;359: The Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM)

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

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%

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

Secondary prevention The purpose of secondary prevention activities such as screening is to identify asymptomatic people with diabetes. Is there an effective intervention that may retard the progression of disease or the severity of its complications?

Screening approaches Population screening Selective screening Opportunistic screening

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

Tertiary prevention Includes actions taken to prevent and delay the development of acute or chronic complications. Acute complications: such as hypoglycemia, severe hyperglycemia and infections. Chronic complications: such as atherosclerosis, retinopathy, nephropathy, neuropathy and foot problems.

Current Scenario Focus on treatment and prevention of complications – secondary prevention ( mainly individual based) Needs a ‘paradigm’ shift- from secondary prevention to primary prevention Three strategies for primary prevention- –Upstream- whole population –Midstream- special high risk groups eg children, elderly etc –Downstream- high risk ‘individuals’

Effective interventions Strict metabolic control, education and effective treatment. Screening for complications in their early stages when intervention is more effective.

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

Obstacles and barriers for prevention Economic problems: unavailability of needed resources. Socio-cultural problems. Lack of data, knowledge and skills.

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

Examples of socio-cultural barriers: Obesity is not considered negatively. No value given to physical exercise. Changing diet is very difficult. No time is granted to do physical exercise at work.

Central issues in Type 2 diabetes prevention Type 2 diabetes prevention must be integrated in a major program addressing the prevention of other lifestyle related disorders like CVD and some cancers. Primary prevention is of the essence especially in resource-constrained countries. Diabetes prevention is an inter-sectoral effort requiring cooperation and coordination.

Central issues in Type 2 diabetes prevention- Cont Diabetes prevention should be addressed within the context of health system reform ensuring the availability of acceptable health care standards. Culturally appropriate and economically feasible interventions should be adopted. Imposing unacceptable or unaffordable interventions will have a negative impact.

What do we know about Type 2 diabetes prevention? Type 2 diabetes is a major challenge to human health. Type 2 diabetes can be prevented. Primary prevention is a suitable and affordable choice. There is strong evidence that lifestyle interventions are effective in diabetes prevention. Barriers for prevention should be addressed.

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

AACE Prediabetes Consensus Statement: Summary Untreated individuals with prediabetes are at increased risk for diabetes as well as for micro- and macrovascular complications Untreated individuals with prediabetes are at increased risk for diabetes as well as for micro- and macrovascular complications Treatment goals are to prevent deterioration in glucose levels and modify other risk factors such as obesity, hypertension, and dyslipidemia Treatment goals are to prevent deterioration in glucose levels and modify other risk factors such as obesity, hypertension, and dyslipidemia –The same blood pressure and lipid goals are suggested for prediabetes and diabetes Intensive lifestyle management is the cornerstone of all prevention efforts; pharmacotherapy targeted at glucose may be considered in high-risk patients Intensive lifestyle management is the cornerstone of all prevention efforts; pharmacotherapy targeted at glucose may be considered in high-risk patients Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):1-53. Garber AJ, et al. Endocr Pract. 2008;14:

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There is a long period of glucose intolerance that precedes the development of diabetes There is a long period of glucose intolerance that precedes the development of diabetes Screening tests can identify persons at high risk Screening tests can identify persons at high risk There are safe, potentially effective interventions that can address modifiable risk factors: There are safe, potentially effective interventions that can address modifiable risk factors: –Obesity –Body fat distribution –Physical inactivity –High blood glucose T2DM, type 2 diabetes mellitus. Garber AJ, et al. Endocr Pract. 2008;14: Feasibility of Preventing T2DM

Lifestyle Intervention in Prediabetes Persons with prediabetes should reduce weight by 5% to 10%, with long-term maintenance at this level A diet that includes caloric restriction, increased fiber intake, and (in some cases) carbohydrate intake limitations is advised. A program of regular moderate-intensity physical activity for minutes daily, at least 5 days a week, is recommended Garber AJ, et al. Endocr Pract. 2008;14:

Interventions Proven to Delay or Prevent T2DM Development T2DM, type 2 diabetes mellitus. Sherwin RS, et al. Diabetes Care. 2004;27,(Suppl 1): S47-S54. Eriksson K-F, Lindgärde F. Diabetologia. 1991;34: Ramachandran A, et al. Diabetologia 2006;49: Knowler WC, et al. N Engl J Med. 2002;346: Defronzo RA, et al. N Engl J Med. 2011;364: Intervention Rate of Conversion to Normal Glucose Tolerance Lifestyle (3 trials)52%-58% Metformin (2 trials)26%-31% Acarbose (1 trial)25% Pioglitazone (1 trial)48%

T2DM Prevention in Women With a History of GDM: Effect of Metformin and Lifestyle Interventions Findings from the DPP: Findings from the DPP: –Progression to diabetes is more common in women with a history of GDM vs those without, despite equivalent degrees of IGT at baseline Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM DPP, Diabetes Prevention Program; GDM, gestational diabetes mellitus; IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus. Ratner RE, et al. J Clin Endocrinol Metab. 2008;93: