Cardiometabolic Syndrome Dr. Nabil Sulaiman HOD Family and Community Medicine, Sharjah University and University of Melbourne & Dr Dhafir A. Mahmood Consultant Endocrinologist Al- Qassimi & Al-Kuwait Hospital Sharjah

Agenda History & Definition Clustering component of Metabolic Syndrome Cardiovascular disease worldwide Global cardiometabolic risks Abdominal obesity prevalence ( National & International ) Intra Abdominal Adiposity & associated risks Targeting Cardiometabolic Risk factors Multiple Risk Factor management A Critical Look at the Metabolic Syndrome

Metabolic Syndrome (History) Kylin first to describe the clustering of hypertension, hyperglycemia, hyperuricemia Himsworth first reported Insulin insensitivity in diabetics Yalow and Berson developed insulin assay and correlated insulin levels & glucose lowering effects in resistant and non-resistant individuals

Metabolic Syndrome History (cont.) Reaven in his Banting lecture at the ADA meeting coined the term Syndrome X and brought into focus the clustering of features of Metabolic Syndrome Reaven now prefers the name, Insulin- Resistance Syndrome - feels insulin resistance is the common denominator for Metabolic Syndrome Literature now extensive

Other Names Used: Syndrome X Cardiometabolic Syndrome Cardiovascular Dysmetabolic Syndrome Insulin-Resistance Syndrome Metabolic Syndrome Beer Belly Syndrome Reaven’s Syndrome etc.

Clustering of Components: Hypertension: BP. > 140/90 Dyslipidemia: TG > 150 mg/ dL ( 1.7 mmol/L ) HDL- C < 35 mg/ dL (0.9 mmol/L) Obesity (central): BMI > 30 kg/M2 Waist girth > 94 cm (37 inch) Waist/Hip ratio > 0.9 Impaired Glucose Handling: IR, IGT or DM FPG > 110 mg/dL (6.1mmol/L) 2hr.PG >200 mg/dL(11.1mmol/L) Microalbuninuria (WHO)

Necessary Criteria to Make Diagnosis WHO: WHO: Impaired G handling + 2 other criteria. Impaired G handling + 2 other criteria. –Also requires microalbuminuria - Albumen/ creatinine ratio >30 mg/gm creatinine IDF: IDF: –Require central obesity plus two of the other abnormalities NCEP/ATP III: NCEP/ATP III: –Require three or more of the five criteria

What is cardiometabolic risk?* Global cardiometabolic risk represents the overall risk of developing type 2 diabetes and/or cardiovascular disease (including MI and stroke), which is due to a cluster of modifiable risk factors/markers These include classical risk factors such as smoking, high LDL, hypertension, elevated blood glucose and emerging risk factors closely related to abdominal obesity (especially intra-abdominal adiposity), such as insulin resistance, low HDL, high triglycerides and inflammatory markers Cardiometabolic risk is based on the concept of risk continuum Cardiometabolic risk is based on the concept of risk continuum * working definition MI: myocardial infarction; LDL: low-density lipoprotein; HDL: high-density lipoprotein

Global cardiometabolic risk* Gelfand EV et al, 2006; Vasudevan AR et al, 2005 * working definition

Despite therapeutic advances, CV disease remains the leading cause of death (USA) Number of deaths (thousands) Male Female % of all deaths (right axis) No. of deaths (left axis) % All deaths (male + female) National Center for Health Statistics, 2004 Data for 2002

Substantial residual cardiovascular risk in statin-treated patients Placebo Statin Year of follow-up % patients Risk reduction=24% (p<0.0001) The MRC/BHF Heart Protection Study Heart Protection Study Collaborative Group, % of statin-treated patients had a major cardiovascular event by 5 years

Abdominal obesity has reached epidemic proportions worldwide Men (%)Women (%)Total (%) US South Europe South Korea Australia South Africa North Europe Prevalence of abdominal obesity by region 1. Ford ES et al, 2003; 2 Haftenberger M et al, 2002; 3. Kim MH et al 2004; 4. Cameron AJ et al, 2003; 5. Puoane T et al, 2002

Targeting Cardiometaboilc Risk Defining cardiometabolic Risk What is Abdominal Obesity ? Can be defined by Waist Circumference; ATP- IIIIDF Male: > 102 Cm. (> 42 Inch ) Female : > 88 Cm. (> 35 Inch ) Male : > 94 Cm. ( > 37 Inch ) Female : > 80 Cm. ( > 31.5 Inch )

Obesity: IDF: IDF: –Central obesity - waist circumference >94 cm for Europid men, >80 Europid women with ethnicity specific values for other groups WHO: WHO: –Waist-hip ratio >0.9 - men or > women ATP III: ATP III: –Waist circumference >40 in. - men, > 35 in. - women

Fat Topography In Type 2 Diabetic Subjects Intramuscular Intrahepatic Subcutaneous Intra- abdominal FFA * TNF-alpha * Leptin * IL-6 (CRP) * Tissue Factor * PAI-1 * Angiotensinogen *

Patients with abdominal obesity often present with one or more additional cardiovascular risk factors (NCEP ATP III criteria) Abdominal obesity is linked to multiple cardiometabolic risk factors National Cholesterol Education Panel/ Adult Treatment Panel III, 2002 Cardiovascular risk factorParameters Increased waist circumferenceMen ≥102 cm (40 in) Women ≥88 cm (35 in) Elevated LDL- Cholesterol Elevated triglycerides > 2.6 mmol/L (> 70 mg/d )  1.7 mmol/L (  150 mg/dL) Low HDL- CholesterolMen <1.03 mmol/L (<40 mg/dL) Women <1.30 mmol/L (<50 mg/dL) Hypertension BP  130/80 mm Hg Elevated fasting glucose  6.1 mmol/L (  110 mg/dL) HDL: high-density lipoprotein; BP: blood pressure

Targeting Cardiometaboilc Risk Defining cardiometabolic Risk 86% At least 1 additional CM risk factor 24% 2 or more additional CM risk factors

Abdominal obesity and increased risk of cardiovascular events Dagenais GR et al, 2005 Adjusted relative risk CVD deathMIAll-cause deaths Tertile 1 Tertile 2 Tertile 3 MenWomen <95 95–103 >103 <87 87–98 >98 Waist circumference (cm): The HOPE study Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C; CVD: cardiovascular disease; MI: myocardial infarction; BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol

Abdominal obesity predicts adverse outcomes such as sudden death Quintile of SAD The Paris Prospective study Empana JP et al, 2004 Quintile SAD (cm)12–1920–2122–232425–35 BMI (kg/m 2 )< – – – – Age-adjusted relative risk Quintile of BMI p for trend = SAD is a better predictor of risk of sudden death than BMI SAD: sagittal abdominal diameter; BMI: body mass index

Abdominal obesity increases the risk of developing type 2 diabetes <7171–75.976–8181.1–8686.1–9191.1–96.3> Relative risk Waist circumference (cm) Carey VJ et al, 1997

Abdominal obesity is linked to an increased risk of coronary heart disease Waist circumference has been shown to be independently associated with increased age-adjusted risk of CHD, even after adjusting for BMI and other cardiovascular risk factors <  <  <  <  < p for trend = Relative risk Quintiles of waist circumference (cm) Rexrode KM et al, 1998 CHD: coronary heart disease; BMI: body mass index

Diabetes in the new millennium Interdisciplinary problem Diabetes

Diabetes in the new millennium Interdisciplinary problem OBESITY

Diabetes in the new millennium Interdisciplinary problem DIAB ESITY

Targeting Cardiometabolic Risk

Intra-abdominal adiposity is a major contributor to increased cardiometabolic risk Kershaw EE et al, 2004; Lee YH et al, 2005; Boden G et al, 2002 Associated with inflammatory markers (C-reactive protein)  Free fatty acids  Inflammation Insulin resistance Dyslipidaemia Increased cardiometabolic risk IAA = high risk fat Secretion of adipokines ( ↓ adiponectin)  IAA: intra-abdominal adiposity

Abdominal obesity: a major underlying cause of acute myocardial infarction Yusuf S et al, 2004 a Proportion of MI in the total population attributable to a specific risk factor; CVD: cardiovascular disease; BMI: body mass index; PAR: population attributable risk; MI: myocardial infarction Cardiometabolic risk factors in the INTERHEART Study PAR (%) a Abdominal obesity predicts the risk of CVD beyond BMI Hypertension 10 Diabetes 20 Abdominal obesity 49 Abnormal lipids

Pouliot MC et al, 1992 IAA: intra-abdominal adiposity; significantly different from 1 non-obese, 2 obese with low intra-abdominal adiposity levels Non-obese Obese low IAA Obese high IAA Time (min) , mmol/L , ,2 1 Area 1,2 Area pmol/L InsulinGlucose Intra-abdominal adiposity and glucose metabolism

Intra-abdominal adiposity is closely correlated with abdominal obesity To assess IAA, the simplest measure of abdominal obesity is waist circumference, which is strongly correlated with direct measurement of IAA by CT scan or MRI, considered to be the gold standard Després JP et al, 2001; Pouliot MC et al, r = IAA Waist circumference (cm) IAA (cm 2 ) IAA: intra-abdominal adiposity; CT: computed tomography; MRI: magnetic resonance imaging

Waist Circumference

Intra-abdominal adiposity and dyslipidaemia Pouliot MC et al, mg/dL Triglycerides Lean HDL-cholesterol Visceral fat (obese subjects) LowHigh Lean Visceral fat (obese subjects) LowHigh HDL: high-density lipoprotein

Adiponectin  in IAA Anti-atherogenic/antidiabetic:  foam cells  vascular remodelling  insulin sensitivity  hepatic glucose output IL-6  in IAA Pro-atherogenic/pro-diabetic:  vascular inflammation  insulin signalling TNF-   in IAA Pro-atherogenic/pro-diabetic:  insulin sensitivity in adipocytes (paracrine) PAI-1  in IAA Pro-atherogenic:  atherothrombotic risk IAA: intra-abdominal adiposity; IL-6: interleukin-6; TNF-α: tumour necrosis factor-α; PAI-1: plasminogen activator inhibitor-1 Marette A, 2002 Properties of key adipokines

Relationship between adiponectin levels and risk of myocardial infarction Pischon T et al, 2004 Relative risk (95% CI) Risk of MI for highest vs lowest quintile of adiponectin Adjusted for age; date of blood draw; smoking + Adjusted for family history; alcohol; exercise + Adjusted for HbA 1C ; CRP; HDL-cholesterol; LDL-cholesterol p<0.001 p= MI: myocardial infarction; HbA 1c : haemoglobin A 1c ; CRP: C-reactive protein; HDL: high-density lipoprotein; LDL: low-density lipoprotein

Targeting Cardiometaboilc Risk Defining cardiometabolic Risk Cardiovascular Disease Abdominal Obesity Glucose intolerance Insulin Resistance Dyslipedemia Hypertension

Targeting Cardiometaboilc Risk Defining cardiometabolic Risk Major Unmet Clinical Need Classical Risk Factors Novel Risk Factors Cluster Risk Factors LDL-C BP Smoking DM-2 Insulin HDL-C TNF & IL-6 Abdominal Obesity Glucose PAI-1 TG Cardiovascular Disease

Targeting Cardiometaboilc Risk Site of Action Mechanisms Addresses Adipose tissues Adiponectin Dyslipidemia Lipogeenesis Insulin resistance Muscle G uptake Insulin resistance Liver Lipogeenesis Dyslipidemia Insulin resistance GI tract Satiety signals Body weight Waist circumference Hypothalamus Food intake Body weight Waist circumference

Linked Metabolic Abnormalities: Impaired glucose handling/ insulin resistance Atherogenic dyslipidemia Endothelial dysfunction Prothrombotic state Hemodynamic changes Proinflammatory state Excess ovarian testosterone production Sleep-disordered breathing

Resulting Clinical Conditions: Type 2 diabetes Essential hypertension Polycystic ovary syndrome (PCOS) Nonalcoholic fatty liver disease Sleep apnea Cardiovascular Disease (MI, PVD, Stroke) Cancer (Breast, Prostate, Colorectal, Liver)

Multiple Risk Factor Management Obesity Glucose Intolerance Insulin Resistance Lipid Disorders Hypertension Goals: Minimize Risk of Type 2 Diabetes and Cardiovascular Disease Goals: Minimize Risk of Type 2 Diabetes and Cardiovascular Disease

Glucose Abnormalities: IDF: IDF: –FPG >100 mg/dL (5.6 mmol. L) or previously diagnosed type 2 diabetes WHO: WHO: –Presence of diabetes, IGT, IFG, insulin resistance ATP III: ATP III: –FBS >110 mg/dL, <126 mg/dL ( mmol/L ) –(ADA: FBS >100 mg/dL [ 5.6 mmol/L ])

Hypertension: IDF: IDF: hypertension –BP >130/85 or on Rx for previously diagnosed hypertension WHO: WHO: –BP >140/90 NCEP ATP III: NCEP ATP III: –BP >130/80

Dyslipidemia: IDF: IDF: –Triglycerides - >150mg/dL (1.7 mmol /L) – HDL - <40 mg/dL (men), <50 mg/dL (women) WHO: WHO: –Triglycerides - >150 mg/dL (1.7 mmol/L) –HDL - 39 mg/dL) women ATP III: ATP III: –Same as IDF

Adipocytokines and Insulin Resistance Adipokines and Metabolic Syndrome

INSULIN MODULATION OF ENDOTHELIAL ACTIVITIES

Insulin Resistance: Hyperinsulinemic individuals are at risk for developing Diabetes, Dyslipidemia, Hypertension & ultimately Cardiovascular disease Patients with Metabolic Syndrome are 3.5 times as likely to die from Cardiovascular disease compared to normal people

Screening/Public Health Approach Public Education Screening for at risk individuals: –Blood Sugar/ HbA1c –Lipids –Blood pressure –Tobacco use –Body habitus –Family history

Life-Style Modification: Is it Important? Exercise –Improves CV fitness, weight control, sensitivity to insulin, reduces incidence of diabetes Weight loss –Improves lipids, insulin sensitivity, BP levels, reduces incidence of diabetes Goals: Goals: Brisk walking - 30 min./day 10% reduction in body wt. 10% reduction in body wt.

Smoking Cessation / Avoidance: A risk factor for development in children and adults Both passive and active exposure harmful A major risk factor for: –insulin resistance and metabolic syndrome –macrovascular disease (PVD, MI, Stroke) –microvascular complications of diabetes –pulmonary disease, etc.

Diabetes Control - How Important? For every 1% rise in Hb A1c there is an 18% rise in risk of cardiovascular events & a 28% increase in peripheral arterial disease Evidence is accumulating to show that tight blood sugar control in both Type 1 and Type 2 diabetes reduces risk of CVD Goals Goals: FBS - premeal <110, FBS - premeal <110, postmeal <180. postmeal <180. HbA1c <7% HbA1c <7%

Overcome Insulin Resistance/ Diabetes: Insulin Sensitizers: –Biguanides - metformin –PPAR α, γ & δ agonists – Glitazones, Gltazars Rosiglitazon, Pioglitazon –Can be used in combination Insulin Secretagogues: –Sulfonylurea - glipizide, glyburide, glimeparide, glibenclamide –Meglitinides - repaglanide, netiglamide

Insulin Insulin Analogues: –Lyspro /Aspart /glulysine used with meals –Glargine & Livemer as basal insulin Continuous Subcutaneous Insulin Infusion (CSII) NPH/Regular, NPH/logs - Mixed or in fixed combinations (70/30, 75/25, 50/50) Insulin combined with oral agents

BP Control - How Important? MRFIT and Framingham Heart Studies: –Conclusively proved the increased risk of CVD with long-term sustained hypertension –Demonstrated a 10 year risk of cardiovascular disease in treated patients vs non-treated patients to be –40% reduction in stroke with control of HTN Precedes literature on Metabolic Syndrome BP. <130/80 Goal: BP. <130/80

Lipid Control - How Important? Multiple major studies show % reductions in cardiovascular disease risk with use of statins and fibrates in the control of hyperlipidemia. Goals:LDL <100 mg/dL (<3.0 mmol /l) Goals: LDL <100 mg/dL (<3.0 mmol /l) (high risk <70 mg/dL- <2.6 mmol/L) (high risk <70 mg/dL- <2.6 mmol/L) TG <150 mg% (<1.7 mmol /l) TG <150 mg% (<1.7 mmol /l) HDL >40 mg% (>1.1 mmol /l) HDL >40 mg% (>1.1 mmol /l)

Medications: Hypertension: –ACE inhibitors, ARBs –Others - thiazides, calcium channel blockers, beta blockers, alpha blockers –Central acting Alfa agonist : Moxolidin Dylipidemia: –Statins, Fibrates, Niacin Platelet inhibitors: –ASA, clopidogrel

Antihypertensive Medications: Angiotensin -converting Enzyme Inhibitors (ACEI) Angiotensin II Receptor (ARB) Blockers Combination with Thiazides, Calcium Channel Blockers, Cardioselective Beta Blockers <130/80 Target BP: <130/80

A Critical Look at the Metabolic Syndrome Is it a Syndrome?* “…too much clinically important information is missing to warrant its designations as a syndrome.” Unclear pathogenesis, Insulin resistance may not underlie all factors, & is not a consistent finding in some definitions. CVD risks associated with metabolic syndrome has not shown to be greater than the sum of it’s individual components. * ADA & EASD

A Critical Look at the Metabolic Syndrome “Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the ‘metabolic syndrome’.” The advice remains to treat individual risk factors when present & to prescribe therapeutic lifestyle changes & weight management for obese patients with multiple risk factors.

Individual metabolic abnormalities among Qatari population according to gender (Musallam et al 08) Men (n = 405) Women (n=412) Variable n(%) n(%) p-Value ATP III Abdominal obesity 227(56.0) 308(74.8) <0.001 Hypertension 143(35.3)156(37.9) Diabetes 77(19.0) 107(26.0) Hypertriglyceridemia 113(27.9) 83(20.1) Low HDL 95(23.5) 121(29.4) 0.055

Individual metabolic abnormalities among Qatari population according to gender Men (n = 405) Women (n=412) Variable n(%) n(%) p-Value None 88(21.7) 74(18.0) – One 103(25.4) 100(24.3) Two 125(30.9) 111(26.9) – Three or more 89(22.0) 127(30.8) – No of components of ATP III

Multivariate logistic regression analysis of factors associated with Metabolic Syndrome according to (ATP III criteria) Odds ratio 95% CI p-Value Age –1.09 <0.001 Female gender – Body Mass Index –1.07 <0.001 Fam his of DM – Smoking –

Prevalence of MeS in different Countries Prevalence (%) SampleYearCountry Arab Americans Oman Jordan Saudi Arabia 17*1998Palestine Qatar 33.4* Turkey ?Iran * Crude rates Mussallam et al. Int J Food Safety and PH 2008

Prevalence of MeS in different Countries Prevalence (%) SampleYearCountry 34* USA Greece South Australia 6.840, S. Korea 10.2* China 33.4* Turkey 41* Chennai India Qatar * Crude rates Mussallam et al. Int J Food Safety and PH 2008

Determinants and dynamics of the CVD Epidemic in the developing Countries Data from South Asian Immigrant studies Excess, early, and extensive CHD in persons of South Asian origin The excess mortality has not been fully explained by the major conventional risk factors. Diabetes mellitus and impaired glucose tolerance highly prevalent.(Reddy KS, circ 1998). Central obesity, ↑ triglycerides, ↓ HDL with or without glucose intolerance, characterize a phenotype. genetic factors predispose to ↑ lipoprotein(a) levels, the central obesity/glucose intolerance/dyslipidemia complex collectively labeled as the “metabolic syndrome”

Determinants and dynamics of the CVD epidemic in the developing countries Other Possible factors Relationship between early life characteristics and susceptibility to NCD in adult hood ( Barker’s hypothesis) (Baker DJP,BMJ,1993) –Low birth weight associated with increased CVD –Poor infant growth and CVD relation Genetic–environment interactions (Enas EA, Clin. Cardiol. 1995; 18: 131–5) -Amplification of expression of risk to some environmental changes esp. South Asian population) -Thrifty gene (e.g. in South Asians)

CVD epidemic in developing & developed countries. Are they same? Urban populations have higher levels of CVD risk factors related to diet and physical activity (overweight, hypertension, dyslipidaemia and diabetes) Tobacco consumption is more widely prevalent in rural population The social gradient will reverse as the epidemics mature. The poor will become progressively vulnerable to the ravages of these diseases and will have little access to the expensive and technology-curative care. The scarce societal resources to the treatment of these disorders dangerously depletes the resources available for the ‘unfinished agenda’ of infectious and nutritional disorders that almost exclusively afflict the poor

Burden of CVD in Pakistan Coronary heart disease Mortality statistics Specific mortality data ideal for making comparisons with other countries are not available Inadequate and inappropriate death certification, and multiple concurrent causes of death

Central obesity: a driving force for cardiovascular disease & diabetes “Balzac” by Rodin Front Back

Developing A New Definition of the Metabolic Syndrome: IDF Objectives Needs: To identify individuals at high risk of developing cardiovascular disease (and diabetes) To be useful for clinicians To be useful for international comparisons

The new IDF definition focusses on abdominal obesity rather than insulin resistance International Diabetes Federation (IDF) Consensus Definition 2005

Why people physically inactive? Lack of awareness regarding the of physical activity for health fitness and prevention of diseases Social values and traditions regarding physical exercise (women, restriction). Non-availability public places suitable for physical activity (walking and cycling path, gymnasium). Modernization of life that reduce physical activity (sedentary life, TV, Computers, tel, cars).

Insulin Resistance: Associated Conditions

Prevalence of the Metabolic Syndrome Among US Adults NHANES Prevalence (%) > 70 Men Women Age (years) Ford E et al. JAMA. 2002(287): Prevalence by IDF vs. NCEP Definitions (Ford ES, Diabetes Care 2005; 28: ) (unadjusted, age 20+) NCEP : 33.7% in men and 35.4% in women IDF: 39.9% in men and 38.1% in women

Prevention of CVD There is an urgent need to establish appropriate research studies, increase awareness of the CVD burden, and develop preventive strategies. Prevention and treatment strategies that have been proven to be effective in developed countries should be adapted for developing countries. Prevention is the best option as an approach to reduce CVD burden. Do we know enough to prevent this CVD Epidemic in the first place.

The new IDF definition focusses on abdominal obesity rather than insulin resistance International Diabetes Federation (IDF) Consensus Definition 2005

Central Obesity Waist circumference – ethnicity specific* – for Europids: Male > 94 cm Female > 80 cm plus any two of the following: Raised triglycerides> 150 mg/dL (1.7 mmol/L) or specific treatment for this lipid abnormality Reduced HDL cholesterol< 40 mg/dL (1.03 mmol/L) in males < 50 mg/dL (1.29 mmol/L) in females or specific treatment for this lipid abnormality Raised blood pressureSystolic : > 130 mmHg or Diastolic: > 85 mmHg or Treatment of previously diagnosed hypertension Raised fasting plasma glucose Fasting plasma glucose > 100 mg/dL (5.6 mmol/L) or Previously diagnosed type 2 diabetes If above 5.6 mmol/L or 100 mg/dL, OGTT is strongly recommended but is not necessary to define presence of the syndrome.

Treatment of Metabolic Syndrome: 2005 Aspirin Diet, Exercise, Lifestyle change Stop smoking CB1 Receptor Blocker Oral hypoglycaemics Antihypertensives Statins & Fibrates Insulin ACEI &/or A2 receptor blockers

Primary management for the Metabolic Syndrome is healthy lifestyle promotion. This includes: moderate calorie restriction (to achieve a 5-10% loss of body weight in the first year) moderate increases in physical activity change dietary composition to reduce saturated fat and total intake, increase fibre and, if appropriate, reduce salt intake. Recommendations for treatment

Appropriate & aggressive therapy is essential for reducing patient risk of cardiovascular disease Lifestyle measures should be the first action Pharmacotherapy should have beneficial effects on –Glucose intolerance/diabetes –Obesity –Hypertension –Dyslipidaemia Ideally, treatment should address all of the components of the syndrome and not the individual components Management of the Metabolic Syndrome

Summary: new IDF definition for the Metabolic Syndrome The new IDF definition addresses both clinical and research needs: provides a simple entry point for primary care physicians to diagnose the Metabolic Syndrome providing an accessible, diagnostic tool suitable for worldwide use, taking into account ethnic differences establishing a comprehensive ‘platinum standard’ list of additional criteria that should be included in epidemiological studies and other research into the Metabolic Syndrome

Lifestyle modification Diet Exercise Weight loss Smoking cessation If a 1% reduction in HbA 1c is achieved, you could expect a reduction in risk of: 21% for any diabetes- related endpoint 37% for microvascular complications 14% for myocardial infarction However, compliance is poor and most patients will require oral pharmacotherapy within a few years of diagnosis Stratton IM et al. BMJ 2000; 321: 405–412.