UNIVERSITY OF LATVIA

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1 UNIVERSITY OF LATVIA FACULTY OF MEDICINE HIGHER PROFESSIONAL EDUCATION PROGRAM IN MEDICINE CLINICAL EVALUATION OF TYPE 2 DIABETES MELLITUS PATIENTS WITH CARDIOVASCULAR DISEASES AND CLINICAL DIFFERENTIATION BETWEEN MYOCARDIAL INFARCTION AND ANGINA IN PATIENTS WITH TYPE 2 DIABETES MELLITUS Author: Poonam KANGLOO Student number: MEDI Supervisor: Prof. Renāte Ligere Reviewer: Prof. Valdis Pīrāgs RIGA 2007

2 CONTENTS Foreword i Abstract ii Kopsavilkums (Abstract in Latvian Language) iii Acknowledgements... iv Abbreviations... v 1. LITERATURE REVIEW Diabetes mellitus in the world Diabetes mellitus in Latvia Clinical presentation of type 2 diabetes mellitus, treatment and complications Cardiovascular complications in type 2 diabetes mellitus Macrovascular complications Microvascular complications High risks for cardiovascular diseases in type 2 diabetes mellitus Conclusions AIMS SUBJECTS AND METHODS RESULTS Evaluation of type 2 diabetes mellitus patients with cardiovascular diseases Characteristics of patients Clinical and laboratory investigations Complications Clinical differentiation between myocardial infarction and angina in type 2 diabetes mellitus patients Evaluation of T2DM patients with MI Evaluation of patients with angina Clinical differentiation between MI and angina Clinical differentiation in males Clinical differentiation in females DISCUSSION Cardiovascular diseases in type 2 diabetes mellitus patients Clinical and laboratory investigations Complications Clinical differentiation between myocardial infarction and angina in type 2 diabetes mellitus patients

3 6. CONCLUSIONS AND RECOMMENDATIONS PROBLEMS AND STUDY LIMITATIONS BIBLIOGRAPHY APPENDICES DOCUMENTARY LIST

4 FOREWORD Type 2 diabetes mellitus has been framed as the king of metabolic disturbances and there is no doubt about it. Complications ranging from head to toes, type 2 diabetes mellitus has a notorious reputation. Currently, we give type 2 diabetes mellitus an additional definition by suggesting it is a cardiovascular disease. Cardiovascular disease is the major cause of mortality and morbidity in modern societies. Type 2 diabetes mellitus is one of the main cardiovascular risk factors and around 80% of those affected will die of coronary heart disease, stroke and peripheral vascular disease, many prematurely. Each year, there are about 3.8 million deaths that are attributable to type 2 diabetes mellitus. The risks are magnified in individuals who have other microvascular complication of diabetes mellitus such as diabetic retinopathy and nephropathy. Type 2 Diabetes mellitus has become a world pandemic. It is spreading rapidly across the globe, affecting people irrespective of their age and race and has turned out to be a major public health problem. According to the World Health Organization, it is suspected that around 200 million people are suffering from diabetes mellitus and this figure is expected to rise to 300 million by 2020 and even 500 million by The main concern about the patients with type 2 diabetes mellitus is up to 50% of all patients are undiagnosed since they remain asymptomatic for many years. Therefore detecting these patients is important for the public health and everyday clinical practice to reduce the complications of diabetes mellitus. Environmental factors and lifestyle changes play a major role in the increasing rates of type 2 diabetes mellitus. Obesity, hypertension and dyslipidemia increase risks of cardiovascular complications in these patients. Early detection of the cardiovascular risk factors, recognizing and managing the cardiovascular complications in type 2 diabetes mellitus patients are now high priority emphasized by governmental bodies, professional institutions and patients advocacy groups, as if this epidemic is not halted or reversed, the impact on both the worldwide population and the healthcare system will be considerable. Since type 2 diabetes mellitus is closely linked with cardiovascular disease and the latter being the leading cause of death in Latvia, the aim of this project is to draw attention to the size of this problem, especially with respect to the complications of diabetes mellitus. Secondly, studies have generally suggested the association of myocardial infarction and angina in patients with type 2 diabetes mellitus. However, no studies have focused on why some patients are more vulnerable to myocardial infarction and the others to angina. A comparative study was undertaken to examine the differences. Identification of such markers may reveal new approaches in the prevention of myocardial infarction and angina in patients with type 2 diabetes mellitus. i

5 ABSTRACT Background: Cardiovascular disease (CVD) is the major cause of morbidity and mortality in Latvia and is partly linked with type 2 diabetes mellitus (T2DM). Aim: Clinical evaluation of T2DM patients with CVD and clinical differentiation between myocardial infarction (MI) and angina in T2DM. Subjects and methods: 109 T2DM patients (49 males, 60 females; mean age 67±10 years) were identified from the cardiology department of Pauls StradiĦs Clinical University Hospital. They presented with angina (n=52), MI (n=40) and heart failure (n=17). Prior to admission, 22% were on insulin therapy (n=24), 40% were on oral hypoglycemics (n=44) and 38% were newly diagnosed with T2DM after presenting with CVD (n=41). The main outcome measures were derived from medical histories, clinical and laboratory investigations. Results: All T2DM patients had at least one CVD risk factor: obesity (97%), hypertension (90%), dyslipidemia (50%), elevated serum creatinine (54%) and decreased glomerular filtration rate (67%). Complications varied with both severity and duration of hyperglycemia (p<0.01). Peripheral neuropathy was the most common complication (55%), affecting all patients after 10 years with T2DM. Nephropathy was already present in newly diagnosed patients with T2DM. Logistic regression models found for low high density lipoprotein (HDL) significantly increased risk of decline in renal function (r=-0.266, p=0.005) and increased serum creatinine (r=-0.403, p<0.0005). Males with MI had higher diastolic pressure (93 v/s 85 mmhg; p=0.045), lower HDL levels (1.09 v/s 1.33 mmol/l; p=0.002) and higher fibrinogen levels (5.06 v/s 4.50 g/l; p=0.014) compared to those with angina. Females with MI were older (72 v/s 66 years; p=0.016) than those with angina, but the latter had higher concentration of D-dimers (369 v/s 237 mkg/l; p=0.023). Conclusions: T2DM patients had multifactorial risk factors for CVD, among were obesity, hypertension, elevated fasting blood glucose and serum creatinine, dyslipidemia and poor renal function. Diastolic hypertension, low HDL levels and high fibrinogen were associated with MI in males. Women after 70 years were more likely to suffer from MI. High concentrations of D-dimers were associated with angina in women before 70 years. ii

6 KOPSAVILKUMS Pamatojums: Kardiovaskulārās slimības (KVS) ir galvenais saslimstības un mirstības cēlonis Latvijā, tās ir daĝēji saistītas ar 2.tipa cukura diabētu (2TCD). Mērėis: 2. tipa diabēta slimnieku ar kardiovaskulārām patoloăijām klīniskā izpēte un klīniskais diferencēšana starp miokarda infarktu (MI) un stenokardiju šo slimnieku vidū. Subjekti un metodes: 109 2TCD pacienti (49 vīrieši, 60 sievietes; vecumā no 67±10 gadiem) tika atlasīti Paula StradiĦa klīniskās universitātes slimnīcas kardioloăijas nodaĝā. ViĦiem tika konstatēta stenokardija (n=52; 48%), MI (n=40; 37%) un sirds māzspējums (n=17; 15%). Pirms iestāšanās 22% slimnieku saħēma insulīna terapiju (n=24), 40% bija orālā hipoglikēmija (n=44) un 38% bija no jauna diagnosticēts T2DM pēc CVD (n=41) konstatēšanas. Galvenie rezultāti bija iegūti no slimības vēsturēm, klīniskajiem un laboratoriskajiem pētījumiem. Rezultāti: Visiem 2TCD pacientiem bija vismaz viens KVS riska faktors: korpulence (97%), hipertonija (90%), dislipidēmija (50%), paaugstināts seruma kreatinīns (54%) un pazemināta kamoliħu filtrācija (67%). Komplikācijas variēja gan ar hiperglikēmijas smagumu, gan ar ilgumu (p=0.01). Periferiālā neiropātija bija visbiežāk sastopamā komplikācija (55%), kura piemeklēja visus pacientus pēc 10 gadu slimošanas ar 2TCD. Slimniekiem, kam 2TCD bija diagmosticēts pirmo reizi jau novērojām nefropātiju. Izmantojot loăistiskās regresijas modeĝus bija atklāts, ka zems augsta blīvuma lipoproteīna (ABL) līmenis būtiski palielināja nieru funkcijas pasliktināšanās (r=0.266, p=0.005) risku un seruma kreatinīna paaugstināšanās līmeni (r=0.403, p<0.0005). Vīriešiem ar MI bija augstāks diastoliskais asinsspiediens (93 v/s 85 mmhg; p=0.045), fibriogēna līmeħi (5.06 v/s 4.50 g/l; p=0.014) un zemāki ABL līmeħi (1.09 v/s 1.33 mmol/l; p=0.002) salīdzinot ar stenokardijas slimniekiem. Sievietes ar MI bija vecākas (72 v/s 66; p=0.016) nekā stenokardijas slimnieces, bet pēdējām bija augstāka D-dimeru koncentrācija (369 v/s 237 mkg/l; p=0.023). Secinājumi: 2TCD pacientiem atrasti multifaktoriālie KVS riska faktori, starp tiem bija korpulence, hipertonija, paaugstināta asins glikoze tukšā dūšā un seruma kreatinīns, kā arī nieru funkcijas pasliktināšanās. Diastoliskā hipertoniju, zemu ABL līmeni un augstu fibrinogēnu novēroja vīriešiem ar MI. Sievietēm vecākām par 70 gadiem paaugstinājās MI risks. Augsta D- dimēru koncentrācija bija sievietēm jaunākām par 70 gadiem bija saistīta ar stenokardiju. iii

7 ACKNOWLEDGEMENTS I would like to extend my gratitude to all the persons, who I did not mentioned but who in one way or the other have contributed to the realization of this research work. It is a great pleasure and privilege to convey my deepest gratefulness and immense admiration to my academic advisor and eventually my thesis supervisor, Prof. Renāte Ligere for her constant guidance, invaluable inspiration, encouragement and continuous support in taking the challenge of this research idea and give this thesis a final shape. My sincere appreciation is also extended to one of the most important figures of the University of Latvia, my referee Prof. Valdis Pīrāgs for his constructive criticism, guidance and continuous encouragement. I am extremely grateful to Mr. Steven Kowlessur, senior pharmacist at St Marys Hospital, London, United Kingdom for his continuous inspiration, technical suggestions and endless support. Without his support this study might not end up with this fruitation. Sincere thanks go to my parents and family for their cooperation and support without whom I would not be studying medicine. Thank you very much for believing in my abilities and supporting me during the whole duration of my studies. I would like to thank the staff of the outpatient department of Endocrinology, Consultation Polyclinic, Nodala 27 and Nodala 36 of the Pauls Stradins Clinical University Hospital for sorting out the list of patients and their medical records. Dr Julie Lin, Assistant Professor of Medicine at the Harvard Medical School, though I do not know her personally, was ready to help me about the renal function, blood glucose and lipoproteins. My wholehearted acknowledgement goes to my colleagues and friends, especially Pramod Kumar Poonit and Kitsee Yeung, who were always ready to help me and supported me with their valuable suggestions and encouragement. My warm wishes go to Prof Nikolajs Sjakste for reading my work, helping me with ideas and motivating me with his lovely words. I would also like to thank Normunds LegzdiĦš, who agreed to help me with the translation of the abstract form English to Latvian without hesitation. Last but certainly not least, I would like to thank Elina Pujate for answering to my statistical questions and giving me ideas to choose the best method. iv

8 ABBREVIATIONS ACE ADA AGEs ALAT ANOVA Apo APTL ARB ARIC ASAT ATP BMI BP CAD CHD CKD CI CRP CVD DCCT DM ECG EU ESRD ESRF FBG GFR HbA1c HDL HF HR - Angiotensin Converting Enzyme - American Diabetes Association - Advanced glycosylation end products - Alanine aminotransferase - Analysis of variances - Apolipoprotein - Activated partial thromboplastin time - Angiotensin II Receptor Blocker - Atherosclerosis Risk in Communities - Aspartate aminotransferase - Adult Treatment Panel - Body Mass Index - Blood Pressure - Coronary Artery Disease - Coronary Heart Disease - Chronic kidney disease - Confidence interval - C- reactive protein - Cardiovascular Disease - Diabetes Control and Complications Trial - Diabetes Mellitus - Electrocardiogram - European Union - End stage renal disease - End stage renal failure - Fasting Blood Glucose - Glomerular filtration rate - Glycosylated (or glycated) hemoglobin - High Density Lipoprotein - Heart failure - Hazard ratio v

9 HT IDF IFG IGT IHD IL LDL MI NHANES OGTT OR PAD - Hypertension - International Diabetes Federation - Impaired Fasting Glucose - Impaired Glucose Tolerance - Ischemic heart disease - Interleukin - Low Density Lipoprotein - Myocardial infarction - National Health and Nutrition Examination Survey - Oral Glucose Tolerance Test - Odds ratio - Peripheral arterial disease PAI-1 - Plasminogen Activation Inhibitor - 1 PCA PVD RR T1DM T2DM TG or Tg TGF UK UKPDS USA VACSDM VEGF VLDL WC WHO - Primary Coronary Angioplasty - Peripheral vascular disease - Relative risk - Type 1 Diabetes Mellitus - Type 2 Diabetes Mellitus - Triglycerides - Transforming growth factor - United Kingdom - United Kingdom Prospective Diabetes Study - United States of America - Veterans Affairs Cooperative Study of Diabetes Mellitus - Vascular endothelial growth factor - Very Low Density Lipoprotein - Waist Circumference - World Health Organization vi

10 1. LITERATURE REVIEW Diabetes mellitus (DM) have been known for centuries. In the past, DM would have been extremely enigmatic to physicians trying to understand the disease, which manifests with strange symptoms. This changed when glucose metabolism and the role of insulin were clarified. Although it was apparently a disease of low prevalence, physicians had observed the very distinctive features of frank diabetes since ancient times but struggled to explain them. Arataeus of Cappadocia is credited with naming the disease in the first century AD on the basis of excessive urination. He got the name diabetes from the Greek word for syphon ( dia- through, bainein to go) [Medvei VC. 1993]. There are multiple forms of diabetes. The most frequently described one is diabetes mellitus, a chronic disorder involving the body's use of blood glucose and the synthesis of the hormone insulin. In recent centuries, DM has turned out to be a major public health problem across the world. It is suspected that around 200 million people are suffering from DM and it is expected to increase to 300 million by 2020 and even 500 million by 2030 [Zimmet PZ. et al.,1997]. Up to 50% of all patients with type 2 diabetes mellitus (T2DM) are undiagnosed since they remain asymptomatic for many years. Detecting these patients is important for the public health and everyday clinical practice [Ryden L. et al., 2007]. DM is a disorder of carbohydrate metabolism. It is characterized by persistent hyperglycemia and is classed as a metabolic disease that needs medical diagnosis, treatment and lifestyle changes. Classification of DM includes etiological types and different clinical stages of hyperglycemia. Four main etiological categories have been identified. Those are: Diabetes type 1, type 2, other specific types and gestational diabetes (occurs during pregnancy) as detailed in the World Health Organisation (WHO) documentation [WHO Consultation, 1999]. Type 1 diabetes mellitus (T1DM) is due to autoimmune destruction of the insulin-producing cells, while T2DM and gestational diabetes are due to insulin resistance by tissues. T2DM may progress to destruction of the insulin producing cells of the pancreas, but is still considered T2DM, even though insulin administration may be required. DM increases a patient's risk for heart attack, stroke, and other complications related to poor circulation. When a patient has several risk factors, besides DM, such as high blood pressure (BP) and dyslipidemia, he or she is at increased risk for a cardiovascular disease (CVD) [Irons BK. & Kroon LA. 2005]. In fact there is a two-fold to four-fold increase in the risk for coronary heart disease (CHD) and stroke when patients are also suffering from T2DM [American Diabetes Association (ADA), 2007]

11 1.1. Diabetes mellitus in the world Facts and figures about DM and its complications [International Diabetes Federation (IDF), 2007; WHO Diabetes Unit, 2007] In 2007, five countries with the largest numbers of people with diabetes are India (40.9 million), China (39.8million), United States of America, USA (19.2million), Russia (9.6million) and Germany (7.4million). In 2007, five countries with the highest diabetes prevalence in the adult population are Nauru (31%), United Arab Emirates (20%), Saudi Arabia (17%), Bahrain (15%) and Kuwait (14%). By 2025, the largest increases in DM prevalence will take place in developing countries. Each year a further 7 million people develop diabetes. Every 10 seconds two people develop diabetes. Every 10 seconds a person dies from diabetes-related causes. Each year 3.8 million deaths are attributable to diabetes. An even greater number die from CVD made worse by diabetes-related lipid disorders and hypertension. Diabetes is the fourth leading cause of global death by disease. At least 50% of all people with diabetes are unaware of their condition. In some countries this figure may reach 80%. Up to 80% of T2DM is preventable by adopting a healthy diet and increasing physical activity. Diabetes is the largest cause of kidney failure in developed countries and is responsible for huge dialysis costs. T2DM has become the most frequent condition in people with kidney failure in countries of the Western world. The reported incidence varies between 30% and 40% in countries such as Germany and the USA. 10% to 20% of people with diabetes die of renal failure. It is estimated that more than 2.5 million people worldwide are affected by diabetic retinopathy. Diabetic retinopathy is the leading cause of vision loss in adults of working age (20 to 65 years) in industrialized countries. On average, people with T2DM will die 5-10 years before people without diabetes, mostly due to CVD. CVD is the major cause of death in diabetes, accounting for some 50% of all diabetes fatalities, and much disability. People with T2DM are over twice as likely to have a myocardial infarction (MI) or stroke as people who do not have diabetes. And, people with T2DM are as likely to suffer from MI as those without diabetes who already had a heart attack

12 Epidemiology and prevalence of DM in the world: Diabetes mellitus has become a world pandemic. T2DM is spreading rapidly across the globe, affecting people irrespective of their age and race. In 2003, it was estimated that the worldwide prevalence of diabetes in people aged 20 to 79 was 5.1 percent (about 194 million). Figure shows the prevalence of DM in the world and the estimated increase in the year Figure 1.1.1: Worldwide prevalence of diabetes mellitus in 2000 [IDF 2007] India has the highest number of people suffering from DM. China and the USA were the top 2 and 3 countries affected with DM in the year In the year 2003, DM was higher in developed countries than in developing countries. In the developing countries, the prevalence was highest in Europe and Central Asia and lowest in Sub- Saharan Africa. The number of people suffering from T2DM in the European region and Western Pacific Region were respectively 48 million and 43 million. India has the highest number of - 3 -

13 people suffering from diabetes. In 2003, it was estimated that 35.3 million people were suffering from it and this is expected to double to 73.5 millions in In 2003, there was an estimated 314 million people in the world (8.2% of the adult population) who were suffering from impaired glucose tolerance (IGT). By 2025, this number is projected to increase to 472 million (9.0% of the adult population). The trend of IGT follows nearly the same pattern as that for diabetes. Nauru has the highest prevalence with 20.4% of the population suffering from IGT. This figure is expected to rise to 21.2% by the Again, India had the highest number of people suffering from IGT (85.6 million), which is expected to rise to 132 million in 2025 [IDF 2007]. Cost implication of DM in the world: It is estimated that the financial impact of DM worldwide, in people in the age range, is about 153 billion dollars, and it could even be in the region of 286 billion. The projected cost in 2025 could be between 213 billion and 396 billion dollars, which could be 7% to 13% of the healthcare budget in the world for the year 2025 [IDF 2007]. The impact of the costs of DM on the health system is high and it is on the increase. In developing countries the indirect costs of the disease are as high, if not higher than the direct medical costs [Barcelo A. 2003; King H. et al. 1998]. As it is predicted that the largest rise in the number of diabetics by 2025 will be among the economically productive ages of 20 to 64, the future indirect costs of DM will be even more than they are now. Reasons for the rise in DM in the world: The increase of DM prevalence is projected to occur because of: Longer life span of the population Diet which is unhealthy and increase in fast foods consumption Overweight and obesity A sedentary lifestyle All over the world, traditional lifestyles and dietary patterns that have sustained people over generations are disappearing. Due to financial constraints, a lot of families are often forced to move away from rural areas and into urban areas to seek employment and a better living, and this characteristic is destined to increase in the future as a result of rapid industrialisation in many countries. These families have to adapt to the new ways of life, making them more prone to developing T2DM

14 1.2. Diabetes mellitus in Latvia Based on the Diabetes Screening Programme [Pīrāgs V. 2005], conducted in 2003, it was found that 4.8% of the population was suffering from impaired fasting glucose (IFG), 3.8% were suffering from IGT, 7.9% were suffering from T2DM and 8.6% were suffering from prediabetes. Figure shows the results of the Diabetic Screening Programme conducted in the year Prevalence % Diabetes Screening Programme DIAscreen in total (2003) 16.5% 4.8% IFG 3.8% IGT 7.9% T2DM T2DM+prediab etes Prevalence % Diabetes Screening Programme DIAscreen among males and females 25 (2003) IFG IGT Females Males T2DM T2DM+predia betes Figure 1.2.1: Percentage prevalence of IFG, IGT, prediabetes and T2DM in Latvia according to the results of Diabetes Screening Programme DIA- screen conducted in 2003 [Pirags V., 2005]. In 2003, there were about 48,000 people who were registered to be suffering from DM in Latvia [Statistics from the Latvian Ministry of Health, Public health analysis in Latvia, 2004]. Up to 90% of them were suffering from T2DM whereas 10% of them were suffering from T1DM. But it is estimated that the number is more than three times higher according to the International Diabetes Federation Europe (IDF). The IDF estimated the prevalence of DM in Latvia was around 9.9% of the population who were in the age of 20 to 79. The majority of diabetics were women (96,000) compared to men (78,000). In 2025, it is expected that the total prevalence will increase to 11.1% with the total for men increasing to 84,000 and women decreasing to 94,000 as shown in table [IDF, 2007]. Table 1.2.2: Prevalence of diabetes in Latvia in 2003 and the expected prevalence in 2025 [IDF, 2007] Population Men Women Crude Population Men Women Crude prevalence prevalence 1,758,000 78,000 96, % 1,610,000 84,000 94, % - 5 -

15 The problem of DM in Latvia is mostly because all diabetic patients do not have access to an endocrinologist as some regional centers do not employ such a specialist. The situation in the capital, Riga, is better as endocrinologists are present in 9 out of the 16 outpatient clinics. In addition, the poorly developed public transport system contributes to the fact that people with diabetes practically can not get to the neighboring region or capital. The estimated cost of diabetes care per capita in 2003 was $398 in Latvia [Petersen S, et al. 2005]. Latvian citizens are entitled to state-funded healthcare. The treatment for diabetes is reimbursed by the social security system implying that patients are prescribed insulin and oral medication free of charge. In contrast, diabetic patients have to pay for half of the cost of the glucose test strips that are needed to monitor their blood glucose. They have to pay about LVL 6-50 ( Euros) each month [Statistics from the Latvian Ministry of Health, Public health analysis in Latvia, 2004], depending on their treatment regime. Subsequently, many patients are not able to afford the cost of monitoring the disease progression. This has resulted in an increase in the incidence of loss of sight, renal complications, gangrene and amputations. As from the year 2005, the Latvian Government had set out the general principles for the pharmaceutical reimbursement system [Statistics from the Latvian Ministry of Health, Public health analysis in Latvia, 2004]. Since then, reimbursement is being provided according to the nature and severity of the disease

16 1.3. Clinical presentation of type 2 diabetes mellitus, treatment and complications Out of all the people suffering from DM, over 90% of adults suffer from T2DM. There are clear genetic determinants, as evidence by the high prevalence of the disease within ethnic groups (especially American Indians, Hispanics, and Asians) and in relatives of people with the disease. In T2DM (previously called adult-onset or non-insulin-dependent diabetes, NIDDM), there is an inadequate secretion of insulin. Often insulin levels are very high, especially in early stage of the disease, but peripheral insulin resistance and increased hepatic production of glucose make insulin levels inadequate to normalize the plasma level of glucose. Insulin production then falls, further exacerbating hyperglycemia. The disease generally develops in adults and is more common in the elderly population. Plasma glucose levels reach higher levels after eating in older than in younger adults, especially after high carbohydrate loads, and take longer to return to normal, in part because of increased accumulation of visceral/abdominal fat and decreased muscle mass. Recently there has been a twist in the age of onset of T2DM. It is becoming increasingly common in children as childhood obesity has become epidemic, especially in the USA. It is estimated about 40 to 50% of new-onset DM in children is now T2DM [Pinhas-Hamiel O. & Zeitler P. 2005]. Risk Factors for T2DM: There are various risk factors that can make an individual more likely to develop T2DM. They are either modifiable or non-modifiable risk factors. Non-modifiable risk factors include: Family history of DM and CVD; age greater than 45 years; ethnic groups (especially Asians, African-Americans and Hispanic Americans); gestational diabetes or delivering a baby weighing more than 4 Kg. Modifiable risk factors: obesity (Body mass index, BMI >30 kg/m2); central obesity; hypertension (HT); dyslipidemia; IGT. Clinical features of T2DM: T2DM may sometimes go undiagnosed for a long time without any symptoms. The symptoms may include the following: polydipsia, polyuria, polyphagia, fatigue, blurred vision, frequent or slow-healing of infections (including urinary tract, vaginal, skin), dry and itchy skin, tingling or numbness in hands or feet, unexplained weight loss, erectile dysfunction in men, drowsiness and coma (in severe cases). Diagnosis of T2DM: Diagnostic tests should use plasma glucose measurements from a venous sample and performed in an accredited laboratory. If symptoms are present (described earlier), the diagnosis can be made on the basis of a single result of blood glucose (fasting blood glucose, - 7 -

17 FBG 7.0mmol/l or 2-hr plasma glucose 11.1mmol/l. If symptoms are not present, two abnormal results on separate days are needed. [WHO Consultation, 1999] Treatment of T2DM: The treatment of T2DM focuses on keeping blood glucose at near-normal levels, which typically includes appropriate diet, exercise, home glucose monitoring, oral medication and/or insulin. Dietary modification can improve many aspects of T2DM, including obesity, HT and insulin release and responsiveness. The improvement in glycemic control is related both to the degree of caloric restriction and weight reduction [Wing RR. et al, 1994]. A low carbohydrate diet can help people who are trying to improve blood glucose control, cholesterol, and lose weight. Regular exercise is also beneficial in T2DM, independently of weight loss. It improves glycemic control due to an increased responsiveness to insulin. Sulphonylureas and biguanides are the first line treatment in newly diagnosed type 2 diabetics. Sulphonylureas, e.g. glibenclamide, work by increasing insulin secretion, decreasing hepatic synthesis of glucose and increasing its muscular uptake. Patients with high FBG and obese patients do less well. Over time many patients cease to respond to it, probably due to the pancreatic cells being exhausted, and will have to resort to further drugs in order to control their hyperglycemia. Biguanides, e.g. metformin, work by decreasing gluconeogenesis and increasing its peripheral utilization. They are the first line treatment in obese patients as they tend to be hyperinsulinemic and could be suffering from insulin resistance making sulphonylureas an unsuitable choice. Alpha-glucosidase inhibitors, e.g. acarbose, work by inhibiting digestion of complex carbohydrates and sucrose. They therefore decrease the rise of postprandial blood glucose and plasma insulin levels. They are used in conjunction with other hypoglycemic agents. Meglitinide analogues, e.g. repaglinide, increase the insulin secretion from pancreatic beta cells. They can be used as monotherapy or in addition to metformin. Glitazones (Thiazolidinediones), e.g. rosiglitazone, work by activating the gamma peroximase proliferators receptor (PPR) in liver and muscle, where 80-90% of insulin-induced glucose removal occurs. They do not stimulate insulin secretion but act against insulin resistance and enhance the action of insulin. Insulin is added to the drug regimen when patients are unable to achieve adequate control of blood glucose with oral antiglycemic drugs. There are several preparations of insulin available and they are used according to patient s preference. These are very short-acting (Novorapid/Humalog), short-acting (Actrapid/Humulin S), medium-acting (Insulatard/Humulin I) and long-acting (Ultratard/Humulin Zn)

18 Complications of T2DM: T2DM can affect every part of the body. It affects the cerebrovascular system leading to stroke. Angina, myocardial infarction (MI) and ischaemic heart disease (IHD) are the results of the effects of DM on the cardiovascular system. The renal system, when affected by DM, gives rise to diabetic nephropathy. Diabetic retinopathy results to impairment of sight. Peripheral arterial disease (PAD) and peripheral neuropathy are respectively due to poor blood supply to the lower limbs and impairment in the sensory neurons, which ultimately result in the formation of ulceration and gangrene. When the autonomic system is affected, emptying of the stomach is slowed down. Diarrhea may even result. Skin complications are very common among DM. Besides bacterial infections, fungal infections, and itching, skin problems like diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic blisters, and eruptive xanthomatosis happen mostly or only to people with diabetes. Finally some men can experience sexual dysfunction. All these complications are illustrated in figure The major diabetic complications Cerebrovascular disease Diabetic retinopathy Bacterial and fungal infectionsof the skin Autonomic neuropathy (including slow emptying of the stomach and diarrhea) Cardiovascular disease Diabetic nephropathy Severe hardening of the arteries (atherosclerosis) Sexual dysfunction Poor blood supply to lower limbs (peripheral vascular disease) Necrobiosis lipidoica Sensory impairment (peripheral neuropathy) Gangrene Ulceration Figure 1.3.1: Representation of the different organs/systems affected due to diabetes mellitus [WHO Consultation, 1999] - 9 -

19 1.4. Cardiovascular complications in T2DM CVD are a major worldwide public health problem and it is the main cause of death in developed countries. It is likely to overtake infectious diseases as the most common cause of death in many parts of the less developed world. CVD is the main cause of death in several countries in the European Union (EU), including Latvia, Estonia, Lithuania, Finland, Greece, Ireland, Poland, Slovakia, Sweden and the United Kingdom (UK). Figure shows the number of males and females dying from CVD in Latvia between the years 1982 to 2002 [IDF, 2007]. Number per 100,000 population Number of men and women (aged 35-74) dying from CHD per 100,000 population in Latvia Men Women Year Figure 1.4.1: Men and women, aged 35-74, (per 100,000 population), dying from CVD in Latvia between the year 1982 to 2002 [IDF, 2007]. There was a steady rise in the death rate in men from 1988 to 1994 which then decreased from 1996 to This was erratic in the case of women dying from coronary heart disease. T2DM as a major risk factor for CVD: DM is a major risk factor for developing CVD. It is responsible for more than 50%, up to 80% of deaths in people with T2DM as well as for very substantial morbidity and loss of quality of life. T2DM can lead to cardiovascular damage in a number of ways [Wilson PW. et al., 1998]. As T2DM progresses, the heart and blood vessels undergo changes and lead to a number of different cardiovascular complications [Tuomilehto J. & Lindstrom J. 2003]. As well as being a risk factor in its own right, T2DM is associated with a higher prevalence of other common cardiovascular risk factors such as HT and dyslipidemia and these factors, in turn, have a more harmful effect in the presence of T2DM. For each risk factor present, the risk of cardiovascular death is about three times greater in people with T2DM compared to those without T2DM

20 Coronary artery disease (CAD) is two to three times more common in diabetic patients than in non-diabetic patients and is more of a problem when it occurs in the former [Fisher M. 2003]. Figure shows the number of death in people with and without DM in the year following a heart attack. Figure 1.4.2: Incidence of deaths in people with and without DM in the year following a heart attack. In men, there is a 10% increase in the death rate if DM is present, while in women this is even higher, with an approximate increase of about 15% in the death rate. These resulted from both the severity and widespread nature of atherosclerosis in DM, combined with other causes of vascular disease in DM such as arterial stiffness, microangiopathy and autonomic neuropathy. [Petersen S. et al., 2005]. DM is connected to 25% of acute MI. Silent MI is also common and the risks of sudden death and heart failure (HF) are also increased. In the case of cerebrovascular diseases, transient ischaemic attacks (TIAs) are two to six times more common in the diabetic population. The prevalence of HT in diabetic patients is 1.5 to 2 times that of the general population [Swidan SZ. & Montgomery PA. 1998]. CAD and stroke associated with HT are four to five times more likely to cause death in diabetic patients. In the UK, 35% of deaths are due to cardiovascular causes, compared with about 60% in those with T2DM patients over 40 years old. DM increases the risk more in women than men, so that the risk of cardiovascular death is equal in both sexes in diabetic patients. With respect to peripheral vascular disease (PVD), people with diabetes have a times increase in the risk of lower limb amputation compared to the general population. The impact of CVD in DM is exacerbated even further by the earlier age of onset of T2DM which is now affecting even to children and adolescents, and carries the threat of early onset of CVD. In addition, advances in insulin therapy have improved the life expectancy of people with T1DM but each year of prolonged life increases the likelihood of cardiovascular complications

21 Categorization of cardiovascular complications of DM: This can be divided into 2 sections: Macrovascular (large vessel disease). Around 80% of patients with DM will die of CVD including CHD, stroke and PVD, many prematurely [Kannel WB. & McGee DL. 1979a; Fisher M. & Shaw KM. 2001; Stamler J. et al., 1993; Haffner SM. et al., 1998]. Microvascular (small vessel disease): It includes diabetic retinopathy, which is the most frequent cause of blindness in the working population in developed countries, and diabetic renal disease (nephropathy). The latter itself is associated with an increased cardiovascular morbidity and mortality and is also the most common cause of chronic renal failure and need for dialysis in many countries. [Borch-Johnsen K. & al., 1985; WHO (Europe) & IDF (Europe), 1990]. Diabetic neuropathy is a condition thought to be caused by a combination of microvascular and metabolic abnormalities. [Barnett A.H., 2005]. Figure illustrates the different cardiovascular complications of T2DM in different vascular beds and some end points related to the progression of the disease. Diabetes mellitus Coronary heart disease Cerebrovascular disease Peripheral vascular disease Microvascular disease Myocardial ischemia TIA Claudication Retinopathy Myocardial infarction Stroke Critical ischemia Nephropathy Heart failure Gangrene Neuropathy Figure 1.4.3: Cardiovascular complications of T2DM in different vascular beds Some of the end points are related to the progression of the disease. These complications are divided into 2 groups namely macro- and microvascular disease. Macrovascular complications result from atherosclerosis and include CHD, cerebrovascular diseases and PVD. Microvascular complications are retinopathy, nephropathy and neuropathy. The mechanism by which DM causes these vascular complications is not fully understood but it is thought that it is due to: toxic effects of hyperglycemia The impact of HT Dyslipidemia Functional and structural abnormalities of small blood vessels. People suffering from DM in addition to CVD and/or PVD will ultimately end up with HF, stroke or gangrene if their blood glucose is not kept within the necessary parameters (blood glucose <7 mmol/l). Retinopathy, nephropathy and neuropathy are the other complications of DM in these patients

22 1.4.1: Macrovascular complications of DM The most important macrovascular complications of DM are: CHD: Any disease of the heart caused by CAD, although it usually refers to MI and angina. Cerebrovascular disease: Damage to the blood vessels in the brain, resulting in TIAs and stroke. PVD: It refers to diseases of blood vessels outside the heart and the brain. It often involves a narrowing of the vessels that carry blood to the muscles. Given the global epidemic of T2DM, the double threat of T2DM and CVD is set to explode unless preventative action is taken. It is noteworthy that, in some Western populations, CVD rates have declined in the overall population but no consistent decline is seen in people with DM [Gu K. et al., 1999]. Atherosclerotic CHD: Insulin resistance accelerates atherosclerosis in T2DM because of abnormal lipid levels, HT and excessive insulin levels. This causes three quarters of patients with T2DM to die from CVD, and 15% to die from stroke. Most people with T2DM have a tendency to develop atherosclerosis in large arteries. They also tend to develop atherosclerosis at an earlier age and more extensively than do people who do not have diabetes. Figure shows the cardiovascular triad resulting from atherosclerosis in patients with DM. Figure 1.4.4: The Cardiovascular Triad in T2DM [IDF, 2007]

23 The risk of developing atherosclerosis is 2 to 6 times higher for people with DM, particularly in women. Women, who have DM, unlike those who do not, are not protected from atherosclerosis before menopause, indicating its relationship with the hormones levels, especially the protective effects of estrogens. Other complications of atherosclerosis include angina, MI, abnormal heart rhythms, HF, kidney failure, stroke, and leg cramps (intermittent claudication). Myocardial Infarction: Diabetic patients are more likely to experience a MI and have been shown to have worse outcomes than non-diabetic patients. It is thought to be due to the prothrombotic and procoagulant state. DM is also associated with a nearly 2-fold higher mortality after an acute MI in the long run. There is also marked increase in mortality after an acute MI, particularly in women [Kenneth J. et al., 2001]. Figure illustrates the survival rate in diabetic patients who suffered an MI. Figure 1.4.5: Percentage of survival in diabetic patients who suffered an MI This is the result of a seven year follow up of 1059 diabetics and 1378 non diabetics. Diabetics with or without a prior MI had a greater mortality from CHD than non-diabetics (42% compared to 16% for those with a prior MI and 15% compared to 2% for those without a prior MI) [Kenneth J. et al., 2001; Haffner SM. et al., 1998] The treatment of post MI in diabetic patients include: thrombolytic agents, such as alteplase, which have been shown to reduce mortality after an acute MI in subjects with DM by up to 42%, with no increase in risk of bleeding or stroke [Fibrinolytic Therapy Trialists' (FTT) Collaborative Group, 1994]. A subgroup analysis following an acute MI has shown that Primary Coronary Angioplasty (PCA) is as successful as in patients with and without DM, and may be more effective than thrombolytic therapy in subjects with DM either with or without acute MI [Thomas K. et al. 1999]. A meta-analysis of platelet inhibitor therapy has demonstrated a 31% reduction in non-fatal re-infarction [Antiplatelet Trialist Collaboration, 1994]. The HOPE study, a large, multi

24 national randomized control trial, showed the benefit of ramipril in 3,577 people with DM. One of the primary outcomes was MI and ramipril lowered the risk of an MI by 22% and total mortality by 24% [Yusuf S. et al., 2000]. Diabetic Cardiomyopathy: DM is associated with adverse cardiac structural effects and increases the risk of incidence of HF [Adams KF. 2001]. One reason for the poor prognosis in patients with both DM and ischemic heart disease seems to be an enhanced myocardial dysfunction leading to accelerated HF [Spector KS. 1998]. Thus, patients with DM are usually prone to congestive HF. There are several factors that probably underlie diabetic cardiomyopathy. Those are: severe coronary atherosclerosis, prolonged HT, chronic hyperglycemia, microvascular disease, glycosylation of myocardial proteins and autonomic neuropathy. Stroke in DM: Mortality from stroke is increased by nearly 3-folds when patients with DM are compared to those without DM [Stamler J. et al., 1993]. In the 12-year follow-up of Japanese men in the Honolulu Heart Program, the risk of stroke increased with age for both diabetic and nondiabetic subjects as shown in figure [Abbott RD. et al., 1987]. The risk was substantially higher among diabetic compared with non-diabetic individuals at almost all ages. Figure 1.4.6: Twelve-Year Incidence of Stroke for Men with or without DM, Honolulu Heart Program [Abbott RD. et al., 1987]. Risk of stroke is higher among diabetics compared with non-diabetics at almost all ages. Antiplatelet agents such as aspirin are effective in decreasing the incidence of stroke, especially among individuals with existing CVD or TIA [Sivenius J. 1992]. Smoking cessation will also decrease the risk of stroke. Surgical therapy for carotid artery stenosis will reduce the risk of stroke but there is no evidence that the surgical therapy is better or worse among patients with DM

25 Peripheral vascular disease: Patients with DM have compromise of blood flow to the extremities which results in PVD. Diabetic patients have a two to four-fold increase in the incidence of PVD. There is an abnormal ankle-brachial blood pressure index in about 15% of those individuals [Hiatt WR. 2001]. The symptomatic manifestations of PVD are intermittent claudication and critical limb ischemia. Patients who have PVD may present with typical ischemic pain of one or more muscle groups, atypical pain or no symptoms. The location of pain in patients with claudication varies with the vessels that are involved. Few examples are Buttock and hip aortoiliac disease Thigh common femoral artery or aortoiliac Upper two-thirds of the calf superficial femoral artery Lower one-third of the calf popliteal artery Foot claudication tibial or peroneal artery Intermittent claudication (derived from the Latin word for limp) is defined as a reproducible discomfort of a defined group of muscles that is induced by exercise and relieved with rest. This disorder results from an imbalance between supply and demand of blood flow that fails to satisfy ongoing metabolic requirements. Two classification systems have been used for lower extremity PVD: the Fontaine system and the Rutherford system. Both are based upon the severity of symptoms and markers or severe disease such as ulceration and gangrene [Dormandy JA. & Rutherford RB. 2000]. The rates of limb salvage following distal bypass surgery are relatively high. Salvage rates of around 80% are reported in the initial presence of tissue loss (gangrene and ulceration) [Gloviczki P. et al., 1994]. There is an increased frequency of distal bypass that is associated with reduced frequency of amputation [Conte MS. et al., 2001]. In order to reduce overall cardiovascular mortality, low dose aspirin ( mg) is indicated for severe PVD [Dormandy JA. & Rutherford RB. 2000]. A revascularization procedure can be attempted in some patients with critical limb ischemia. This can be performed by means of a percutaneous transluminal angioplasty. Iloprost, a synthetic prostacyclin, is the only pharmacological agent that has had some positive effect on the prognosis of patients with critical limb ischemia. It has been shown to improve rest pain and ulcer size when compared to placebo [Loosemore T. et al., 1994]. Diabetic Foot: People with DM are at risk of nerve damage (neuropathy) and problems with the blood supply to the feet (ischemia). Combination of neuropathy and ischemia lead to foot ulcers and slow-healing wounds which, if they get infected, may result in amputation. Extensive epidemiological surveys have indicated that between 40% and 70% of all lower extremity

26 amputations are related to DM. This means that every 30 seconds a lower limb is lost to DM. The vast majority (85%) of all diabetes-related amputations are preceded by foot ulcers. [ADA, 2004; International Working Group on the Diabetic Foot, 2003; Jeffcoate WJ. & Van Houtum WH. 2004; Jeffcoate WJ. & Harding KG. 2003]. Based on UK population surveys, diabetic foot problems are a common complication of DM with prevalence of 23-42% for neuropathy, 9-23% for vascular disease and 5-7% for foot ulceration. Amputation rates are higher in patients with DM than non-diabetic patients [Williams and Airey, 2000]. There is good evidence that the tricyclic antidepressants (TCAs) amitriptyline, imipramine and desipramine, the anticonvulsant carbamazepine and topical capsaicin are more effective than placebo in reducing symptoms of painful diabetic peripheral neuropathy and the progression of diabetic foot [McQuay H. et al., 1995]. TCAs should be used as the first line therapy in painful diabetic neuropathy. Gabapentin is also recommended in painful diabetic neuropathy and is associated with fewer side effects than TCAs and older anticonvulsants. Topical capsaicin should be considered for the relief of localized neuropathic pain

27 Microvascular complications of DM Hyperglycemia is a major cause of microvascular complications. The exact mechanism of microvascular disease is still unclear. The main sites to be affected are the retina, the renal glomerulus and the nerve sheath leading respectively to retinopathy, nephropathy and neuropathy. Diabetic retinopathy: Almost one in five newly diagnosed patients with T2DM already has retinopathy. It is the most common specific complication of DM, occurring when the small blood vessels supplying the retina become diseased and close off. Other vessels dilate in order to compensate for the reduced blood supply. These dilated vessels leak, causing diabetic maculopathy. This is a swelling of the macula, the small area of the retina where the best vision is concentrated. Retinopathy is present in almost all patients who have had diabetes for over 20 years. It is usually asymptomatic, with no vision loss in the early stages, unless macular edema is present. If left untreated, about 60% of eyes with proliferative retinopathy (the most severe form) become blind within five years. It is the main cause of blindness in the UK. However, according to the United Kingdom Prospective Diabetes Study (UKPDS), good glycemic control (HbA1c ideally around 7%) and BP control (<130/85 mmhg) should be maintained to prevent onset and progression of diabetic eye disease [UKPDS Group, 1998]. Laser photocoagulation therapy is an effective treatment for proliferative retinopathy [Ferris F. 1996], if applied early enough. It can also be helpful in more than half of maculopathy cases. Diabetic nephropathy: Diabetic nephropathy is defined by a raised urinary albumin excretion of >300 mg/day (indicating clinical proteinuria) in a patient with or without a raised serum creatinine level and with co-existing diabetic retinopathy. It is insidious and asymptomatic until it is well advanced. It is a major cause of mortality in people with T2DM, ranging from 25% in Europeans to 50% in African Caribbeans and South East Asians. Higher incidences may be due to a higher frequency of arterial HT in African Caribbeans and a younger age of onset of T2DM in South East Asians. Clinical symptoms of diabetic nephropathy develop over 5 to 15 years, and can lead to endstage renal failure (ESRF), which is fatal without transplantation or dialysis. People with DM account for up to a quarter of kidney transplants worldwide. Glomerular filtration rate (GFR) is abnormal in approximately half of patients who have been diagnosed with T1DM for less than 5 years. GFR results are 25 to 50 % above the normal [Bank N. 1991]. Those patients with glomerular hyperfiltration appear to be at increased risk for diabetic renal disease [Rudberg S. et al., 1992]. This is particularly true for overt nephropathy if the initial GFR is above 150 ml/min; in comparison, lesser degrees of hyperfiltration may have a

28 slower course, with a lesser risk for microalbuminuria. This is different for T2DM. The degree of hyperfiltration (average of 117 to 133 ml/min) is less than those seen in T1DM. T2DM patients are also older and more likely to have arteriosclerotic vascular disease which will limit increase in both glomerular filtration and glomerular size [Gambara V. et al., 1993]. Tight BP control lower than 130/85 mmhg minimizes the progressive loss of renal function. Angiotensin-Converting Enzyme inhibitors (ACE inhibitors) are more effective than other agents in reducing urinary albumin loss [Kasiske BL. et al., 1993]. It was shown that treatment with an ACE inhibitors for 4.5 years in T2DM patients with microalbuminuria can reduce cardiovascular events by 25% in both those with normal serum creatinine levels and in those with mild renal insufficiency [Mann JFE. et al., 2001]. Diabetic neuropathy: Diabetic neuropathy affecting the feet is common and can lead to ulcers and gangrene of toes, feet or legs in those with poor blood supply. Neuropathy affecting the sensory nerves can cause pain in the shins and soles of the feet and also skin tenderness and feeling of numbness. This pain can be sharp, stabbing or burning. The pain of diabetic neuropathy does not respond to conventional analgesics and can be distressing. The treatment is similar to the management of the diabetic foot (described earlier). It is advisable to have regular screening of the feet as part of an annual diabetes review to identify sensory loss, foot discoloration, evidence of poor circulation and areas of pressure and skin breakdown. It is hoped this will hinder the progression to more serious foot problems. Neuropathy affecting the autonomic nerves can cause gastrointestinal dysfunction, which is treated with metoclopramide or domperidone, and lack of sweating of the feet. Some men can also suffer from erectile dysfunction, needing pharmacological therapy, e.g. sildenafil citrate to help during sexual intercourse

29 1. 5. High risks for cardiovascular diseases in type 2 diabetes mellitus patients Prospective studies indicate that all of the major cardiovascular risk factors, eg cigarette smoking, HT, and high serum cholesterol continue to act as independent contributors to CVD in patients with DM. Clustering of metabolic risk factors, called the metabolic syndrome, occurs commonly in T2DM. The onset of hyperglycemia in patients with the metabolic syndrome appears to accelerate atherogenesis, possibly by enhanced formation of glycosylated proteins and advanced glycation products and/or by increasing endothelial dysfunction. These direct consequences of hyperglycemia probably contribute to the microvascular disease underlying nephropathy and retinopathy, and they may also promote macrovascular disease. Predisposing risk factors for CVD in DM: Several predisposing factors simultaneously affect the development of CVD and DM. Among these concomitant factors are obesity, physical inactivity, heredity, sex, and advanced age. The mechanisms whereby they predispose to chronic diseases are complex and often overlap. These predisposing factors exacerbate the major risk factors like dyslipidemia, HT, and glucose tolerance; and they may cause CVD and DM through other pathways as well. To a large extent, both CVD and DM must be prevented through control of the predisposing risk factors. Modification of life habits is at the heart of the public health strategy in preventing CVD and DM. High priorities are the prevention (or treatment) of obesity and promotion of physical activity. Drug therapy nonetheless may be required to control the metabolic risk factors, particularly when they arise from genetic aberration and aging. Effective drugs are currently available for treatment of HT and dyslipidemia. Hypoglycemic agents also are available for treatment of T2DM, but new pharmacological strategies are under investigation for more effective treatment and prevention. Dyslipidemia: The most common type of dyslipidemia in T2DM is the combination of elevated triglycerides (TG), decrease high density lipoprotein (HDL) and elevated low density lipoprotein (LDL) [Syvanne M. & Taskinen MR. 1997]. High TG levels and low HDL cholesterol were found to be closely related to all CHD events and to coronary mortality in a large cohort of patients with T2DM followed for 7 years [Lehto S. et al., 1997]. The Scandinavian Simvastatin Study (4S) demonstrated that cholesterol-lowering therapy was highly effective with significant reductions in cardiovascular deaths, cardiovascular events, and the need for revascularization procedures. These effects appeared more marked in patients with diabetes than those without diabetes (risk reduction 55% vs. 32%) [The Scandinavian Simvastatin Survival Study (4S), 1994]

30 Obesity: Obesity, defined as a body mass index (BMI) over 30kg/m2, now affects about 20% of the UK adult population and over 30% of the US population [IDF, 2007]. It is one of the most important reasons for the huge increase of T2DM around the world. This follows a similar pattern in children. Figure illustrates the worldwide prevalence of overweight and obesity among school age children (5-17 years) [IDF, 2007]. This increases the risk of T2DM even at younger age and is becoming increasingly common in children as childhood obesity has become epidemic. 40 to 50% of new-onset DM in children is now T2DM [Pinhas-Hamiel O. & Zeitler P. 2005]. Figure Worldwide prevalence of overweight and obesity among school age children (5-17 years) [IDF, 2007]. In USA, about a third of children in this age group are either obese or overweight The goals of therapy for overweight and obese people with diabetes are to lower body fat, and maintain a healthy or lower body weight for the long term, and prevent weight regain. A modest weight loss of 5 to 10% of initial body weight can substantially improve insulin sensitivity, glycemic control, high BP and dyslipidemia [Scheen AJ. & Lefèbvre PJ. 2000]. Sibutramine and Orlistat have been shown to be effective in obese people with T2DM, improving glycemic and metabolic control, and resulting in favorable changes in lipid levels, BP and fat distribution [Haffner SM. 1992]. Metabolic Syndrome: Many studies have shown that hyperinsulinemia and/or insulin resistance are related to various metabolic and physiological disorders including HT, dyslipidemia, and T2DM [IDF, 2004]. This syndrome has been termed Syndrome X or Metabolic Syndrome. In 2004, the IDF proposed a set of metabolic syndrome criteria [IDF, 2004]. Central obesity is an essential element in this definition, with different waist circumference (WC) thresholds set for different race/ethnicity groups: Increased WC 94 cm for Europid men and 80 cm for Europid women