Risk factors and complications of type 2 diabetes in Asians Rajbharan Yadav, Pramil Tiwari* and Ethiraj Dhanaraj Department of Pharmacy Practice National Institute of Pharmaceutical Education and Research Sector 67, S.A.S. Nagar, Punjab, India-160062 * Corresponding author Dr. Pramil Tiwari, e-mail: ptiwari@niper.ac.in Type 2 diabetes mellitus is the commonest form of diabetes constituting 90% of the diabetes population. The acute and chronic complications of diabetes mellitus are major causes of hospital admissions. Studies identified that the prevalence of microvascular and macro vascular complications were more in Asians when compared to Europeans. Common risk factors like greater duration of diabetes, hypertension, poor metabolic control, smoking, obesity and dyslipidemia were more prone to develop diabetic complications. Microvascular diseases were common amongst patients at diagnosis In India. The morbidity and mortality caused by diabetes mellitus can be reduced by secondary prevention through regular screening, early detection, and appropriate treatment of chronic complications. Introduction Type 2 diabetes mellitus (T2DM) is the commonest form of diabetes constituting 90% of the diabetic population. The global prevalence of diabetes is estimated to increase from 4% in 1995 to 5.4% by the year 2025 1. The World Health Organization has predicted that the major burden will occur in the developing countries and there will be a 42% increase (from 51 to 72 million) in the developed countries and 170% increase (from 84 to 228 million) in the developing countries. The countries with the largest number of diabetes patients are, and will be in the year 2025, India, China and United States 1, 2, 3. The number of diabetes patients in India currently around 40.9 million is expected to rise to 80 million by 2030 4. In developing countries, the majority of diabetes patients are in the age range of 45-64 years whereas in the developed countries are aged > 65 years 3. The so-called Asian Indian Phenotype refers to certain unique clinical and biochemical abnormalities in Indians which include increased insulin resistance, higher waist circumference despite lower body mass index, lower adiponectin and higher high sensitive C-reactive protein levels. This phenotype makes Asians more prone to diabetes and premature coronary artery disease 4. The acute and chronic complications of diabetes mellitus are major causes of hospital admissions. Asian patients had more evidence of macro and micro vascular disease at diagnosis of diabetes 8. Several studies showed that the prevalence of microvascular and macrovascular complications were more in Asians when compared to Europeans 8. Lifestyle modifications such as weight control, increased physical exercise, and smoking cessation are also potentially beneficial in preventing diabetes mellitus and coronary artery disease 5. In this review the risk factors and complications in type 2 8 diabetes mellitus in Asians are discussed. Microvascular complications Microvascular complications include retinopathy, nephropathy, and neuropathy. Diabetic retinopathy (DR) can be defined as damage to microvascular system in the retina due to prolonged hyperglycaemia. Diabetic retinopathy is primarily classified into non proliferative diabetic retinopathy (NPDR), or background retinopathy, and proliferative diabetic retinopathy (PDR). Progression from mild form characterized by increased vascular permeability, to moderate, and then to severe NPDR characterized by vascular closure and an increased risk for the development of PDR distinguished by the growth of new blood vessels on the retina and posterior surface of the vitreous. Visual impairment in diabetic retinopathy occurs due to diabetic macular edema (DME) and PDR 6, 10. Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. Nephropathy is the leading cause of chronic renal failure worldwide and is responsible for renal failure in about one third of patients who undergo dialysis. One of the initial markers of this condition is microalbuminuria, which indicates an increased risk of progression to nephropathy as well as an elevated risk of cardiovascular events 5. A test for the presence of microalbumin should be performed at diagnosis in patients with T2DM. Screening for microalbuminuria can be performed by three methods: 1) measurement of the albumin-to-creatinine ratio in a random spot collection; 2) 24 h urine collection with creatinine, allowing the simultaneous measurement of creatinine clearance and 3) timed (e.g., 4 h or overnight) collection 7. The diagnostic criteria for the albuminuria are summarized in Table 1.
Table 1 Definitions of abnormalities in albumin excretion Category Spot collection 24h collection Timed collection (μg/mg creatinine) (mg/24 h) (μg/min) Normal <30 <30 <20 Microalbuminuria 30 299 30 299 20 199 Clinical albuminuria >300 >300 >200 Ref; (7) Diabetic neuropathies are a family of nerve disorders caused by diabetes. It can be classified as peripheral, autonomic, proximal, and focal. Each affects different parts of the body in different ways. Diabetic foot ulcers may develop, mainly because of the abnormal distribution of pressure. The early detection of diabetic neuropathy results in less hospitalization of patients with foot ulcers and fewer lower-extremity amputations 5. Screening for neuropathy can be done reliably by using the 10-g Semmes-Weinstein monofilament over 10 areas of the feet, ankle reflexes and vibration perception over the great toe and ankle. A standard neuropathy disability score (NDS) will be measured and a score of over 6 shows the presence of significant neuropathy is present. One of the most common complications of diabetes in the lower extremity is the diabetic foot ulcer which is often ignored. Diabetes patients are victims of a number of problems specific to their disease that results in increased amputation rates because of the complications of neuropathy and infection. The risks of these all microvascular conditions can be significantly reduced by optimizing glycemic control and if they are detected and treated early through patient education and regular screening 8,13. Macrovascular complications Macrovascular complications include coronary artery disease (CAD), Peripheral vascular disease (PVD), and cerebrovascular events (CVA). Diabetes mellitus is an independent risk factor for the development of atherosclerosis. On the other hand, atherosclerotic or macrovascular disease is responsible for more than 50% of all deaths in patients with T2DM. Cardiovascular disease accounts for most cases of diabetic macrovascular complications and the remaining are caused by cerebrovascular events and peripheral vascular disease 5. In India, escalating population levels of major coronary risk factors have contributed to the coronary heart disease epidemic. Several studies shows that parallel to the increase in Chronic Heart Disease (CHD) in Indian urban populations there has been an increase in prevalence of hypertension, diabetes, high LDL cholesterol, low HDL cholesterol and the metabolic syndrome 11. Mortality among diabetic patients with CAD is higher than non-diabetic subjects. Studies have also shown that myocardial infraction in diabetics was more common than non-diabetics 12. Indian seems to be more predisposed to both diabetes and CAD. PVD is defined as disease of any blood vessel that is not part of heart or brain. The more common form of PVD is observed in lower extremity which is termed as the Lower extremity arterial disease (LEAD). The simplest screening test for PVD is palpitation of peripheral pulses and this is the usual clinical tool to assess the occlusive arteries in peripheries. Absence of peripheral, tibial, popliteal or femoral pulses on peripheral examination are clinically significant. Several techniques used for diagnosis of PVD are angiography, colour duplex ultrasound, and continuous waveform doppler 13. Hypertension is the primary preventable cause of the two major causes of mortality: coronary artery disease (CAD), and cerebrovascular disease (CVD). It increases the risk for CAD by two fold, CVD by seven folds and congestive heart failure by four fold. There is ample evidence for a consistent gradient relationship of blood pressure with CVD and CAD. Studies have also shown that an increase of blood pressure of 5 mm Hg is associated with a 34% increase in risk for CVD and a 21% excess risk for CAD 14,15. Other complications Depression is twice as much common in people with diabetes as in the general population and major depression is present in at least 15% of patients with diabetes. Depression is associated with poorer glycemic control, health complications, decreased quality of life and increased healthcare costs. People with diabetes should be screened for depression regularly, either with direct questioning (e.g. during the past month, have you often been bothered by feeling down, depressed, or hopeless? and during the past month, have you often been bothered by little interest or pleasure in doing things? ) or with a standardized questionnaire 16. The other complication in diabetic men is erectile dysfunction (ED) and the prevalence was 34 to 45%. Risk factors include increasing age, duration of diabetes, poor glycemic control, cigarette smoking, hypertension, dyslipidemia and cardiovascular disease. Microvascular, macrovascular complications, psychological and situational factors may also cause or contribute to ED. In addition to this ED is a side effect of many drugs commonly prescribed to men with diabetes, such as antihypertensive (beta-blockers and thiazide diuretics) and antidepressants. All adult men with diabetes 9
should be periodically screened for ED with a sexual function history and screening for ED in men with T2DM should begin at diagnosis of diabetes 17. Prevalence of microvascular and macrovascular complications Long-standing diabetes mellitus is associated with an increased prevalence of microvascular and macrovascular diseases. With the rising prevalence of diabetes, the numbers suffering from the vascular complications of diabetes will also increase 2. A study was conducted in India on prevalence of microvascular and macrovascular complications in T2DM patients. It was found that prevalence of retinopathy (23.7%), among which background retinopathy was 20% and proliferative was 3.7% 2,3. In Hong Kong, a cross-sectional study was conducted, which revealed the 19% nonproliferative and 3% proliferative retinopathy 4. The prevalence of retinopathy between 1990 and 1996 for patients with newly diagnosed T2DM was 22% in Hong Kong 5. The prevalence of nephropathy in India was less (8.9% in Vellore, 5.5% in Chennai) when compared with the prevalence of 22.3% in Asian Indians in the UK 2. The prevalence of diabetic nephropathy was 30.3% followed by chronic interstitial nephritis (23%) and chronic glomerulonephritis (17.7%) in chronic renal failure patients 1. The prevalence of neuropathy in Indians was 27.5%, which was more when compared to that in Hong Kong (13%) 4. A study had indicated that the risk of CVD was 3-fold higher in nephropathy group than in the nonproteinuric subjects (39 vs. 13.2%). The prevalence of CVD in India was found to be 11.4%, which was higher than other Asian countries 2. Another study showed that the prevalence of CVD indicated by major Q wave changes was found to be 3.9%, which was similar to the prevalence in the Asian Indians in UK (4.0%) 2. Prevalence of PVD in Asian Indians is comparatively low compared with the white population (9.3%). Low prevalence of PVD was demonstrated in Indian patients (4.0%). Although the prevalence of PVD is low, but the neuropathy is very common and is an associated risk factor for diabetic foot infections. Hypertension develops in people with T2DM at the rate twice than those who are non-diabetic. Hypertension is a major contributor to atherosclerotic diseases and can lead to a more rapid progression of nephropathy and renal failure. The prevalence of hypertension was 38 % in Indians while CVA was only noted in 0.9% type 2 diabetes patients 12. Diabetes and its complication in young subjects between different parts of Asian countries shows the prevalence of diabetic retinopathy was significantly lower in younger Indians (5.3%) compare to other ethnic groups like Malaysia (10.8%) and China (15.1%) 6. It was estimated that diabetic foot ulcer was the most expensive complication and approximately 40 to 72 % of all lower extremity amputations were related to diabetes. Recurrence rates for foot ulcer in neuropathic subjects were estimated at 52 % in a study carried out in 374 patients in southern India 4. A comparative study of Asians vs Europeans and Americans was conducted which concludes that the prevalence of macrovascular disease was higher in Asians compared to Europeans (Table 2). Asian patients had more evidence of macro and micro vascular disease at diagnosis of diabetes, compared to European patients. History of ischemic disease was significantly more common in Asians and Americans 8,20. Microvascular diseases were more common amongst Asian patients at diagnosis. Asians had significantly more background retinopathy at diagnosis, including proliferative retinopathy (3.6% vs. 1.6%) 8. Asians and Americans also had a significantly higher prevalence of microalbuminuria and macroalbuminuria, although serum creatinine was similar between two groups. Neuropathy was more in the American patients, although this was not significant 19. Table 2: Prevalence of Micro/Macrovascular complications in Asian and European Complications European Americans Asian Microvascular Neuropathy (%) 6.3 16.9 3.0 Microalbuminuria (%) 5.5 14.5 13.3 Macroalbuminuria (%) 2.3-4.8 Background Retinopathy (%) 6.3 7.6 13.9 Proliferative retinopathy (%) 1.6-3.6 Macrovascular H/O Ischaemic disease (%) 8.7 13.9 12.1 Evidence of Macrovascular disease (%) 9.7 6.0 15.7 Ref; (8,19) 10
Risk factors The important risk factors for the high prevalence of diabetes include: (1) High familial aggregation, (2) Obesity especially central obesity, (3) Insulin resistance and metabolic syndrome, (4) Life style changes due to urbanization 2, (5) Gestational diabetes. Several studies in India and abroad have shown that nearly 75% of the T2DM patients have first degree family history of diabetes, this indicates a strong familial aggregation in the Indian diabetic patient. Insulin resistance has been demonstrated to be a characteristic feature of Asian Indians 3. A comparative study of Asian Indians, Europeans and other ethnic groups have shown that the Asian Indians have higher insulin response than others, at fasting and in response to glucose. Insulin resistance and the compensatory increase in insulin secretion bring about a state of chronically increased insulin and glucose levels in the blood (hyperinsulinemia and hyperglycemia) and thus is a predecessor for diabetes 8. Central adiposity indicates deposition of large quantities of abdominal fat, which consists of visceral fat and subcutaneous fat. Visceral fat increases the risk of diabetes and hyperlipidaemia by favouring insulin resistance. In several ethnic populations including the relatively non-obese Asians population, the android pattern of body fat, typified by more upper body adiposity measured as waist:hip ratio was found to be a greater risk factor for T2DM than general obesity 2, 11. Another study concluded that a continuous positive relationship of all markers of obesity (body-mass index, waist size and waist:hip ratio) with major coronary risk factorshypertension, diabetes and metabolic syndrome while waist hip ratio also correlates with lipid abnormalities 11. Urbanization has brought several changes in the life style in most urban areas in India and it is associated with greater prevalence Table 3: Cardiovascular risk factors in European, Americans and Asian Review Article of diabetes and coronary risk factors in populations of developing countries and is considered a proximate coronary risk factor 8,11. Gestational diabetes is a strong risk factor for diabetes 11. Risk factors for development of complications One study by Harney F et al suggested that some common risk factors like greater duration of diabetes, hypertension, poor metabolic control, smoking, obesity and hyperlipidemia were more prone to develop diabetic complications 10. T2DM increases the risk of coronary events two fold in men and four fold in women. Part of this increase is due to the frequency of associated cardiovascular risk factors such as hypertension, dyslipidemia, and clotting abnormalities. In observational studies, people with both diabetes and hypertension have approximately twice the risk of cardiovascular disease as nondiabetic people with hypertension 20. In a retrospective study done by Klag et al it has been found that elevations of blood pressure are a strong independent risk factor for end-stage renal disease and interventions to prevent the disease need to emphasize the prevention and control of both high-normal and high blood pressure. 21 A comparative study was conducted for assessment of cardiovascular risk factors (Table 3) has shown that Asians had a slightly lower BMI, but significantly greater waist: hip ratio. Asians showed a trend towards higher systolic and diastolic blood pressures, possibly due to more patients with nephropathy, but this was not significantly different 8. Total cholesterol and LDL cholesterol levels were very similar between all three groups, but HDL cholesterol was significantly lower and triglycerides significantly higher in Asian patients 8. Current smokers were more common in Americans (15.4%) whereas Asians were more at risk of Risk factors Europeans Americans Asians Current smokers (%) 22.0 15.4 3.6 Body mass index kg/m 2 27.2 ± 5.3 29.8±5.3 26±5.4 Waist : hip ratio 0.90 ± 0.2 0.92±0.08 0.95±0.2 Systolic BP (mmhg) 123 ± 12-127±10 Diastolic BP mean (mmhg) 76±7-80±5 LVH on ECG (%) 1.6-1.2 Total cholesterol (mg/dl) 209±46 212±38.6 201±50 LDL cholesterol (mg/dl) 135±27 138±37.1 127±31 HDL cholesterol (mg/dl) 50±7.8 50±15.4 37±11.6 Triglycerides (mg/dl) 133±35 151±35 168±44 CHD risk (%) 4.7-7.2 Ref; (8,19) 11
Table 4: Cardiovascular risk factors in Type 2 diabetes Non-modifiable risk factors Age Male sex Family history Newer risk factors Lipoprotein Homocysteine Plasma fibrinogen Tissue plasminogen activator Plasminogen activator inhibitor-1 C-Reactive protein Ref; (2) CHD among all three groups 19. Another study was conducted in Asians has shown that prevalence of cardiovascular risk factors were in the order of central adiposity, dyslipidemia, hyperinsulinemia, glucose intolerance, obesity and hypertension 9. Cardiovascular risk factors in diabetes patients are summarized in table 4: Preventive Measures Lifestyle modification such as weight control, increased physical exercise, and smoking cessation which are potentially beneficial in preventing diabetes mellitus and its complication 5. People should be encouraged to adopt the preventive interventions of diabetes like maintaining normal body weight (BMI 18.5 24.9 kg/m2), engage in regular aerobic physical activity such as brisk walking (at least 30 min per day, most days of the week), limit consumption of alcohol and consume a diet rich in fruits, vegetables, low fat dairy products. Several studies of community-based non communicable disease prevention projects attempted to prevent the onset of diabetes through life style modification, reduction in obesity or through pharmacological mean and clearly demonstrated risk factors reduction by healthy life style bring a huge benefit to the public 22. Community-based strategies for prevention of diabetes are following: 1) primary prevention, 2) secondary prevention, 3) tertiary prevention. Among three former one related with lifestyle modifications. The primary prevention includes two approaches, high risk approach and population approach. The high risk strategy primarily aim to bring preventive care to individuals with a family history of diabetes who carry a genetic susceptibility, individuals with impaired glucose tolerance, aging individuals, sedentary individuals and obese proportion of population. Population strategy aims to lower the mean level of risk for the entire population by increasing 12 Modifiable risk factors Cigarette smoking Obesity Diabetes Elevated cholesterol Hypertension Behavioural risk factors Protective factors Exercise HDL cholesterol Stress reduction physical activity, improving diet and reducing obesity 23. Conclusions Type 2 diabetes mellitus has rapidly become a global health problem with rapid worldwide increasing population growth, aging, urbanization and increasing prevalence of obesity and physical inactivity indicating the urgent need to prevent diabetes and its complications rather than simply treat it, once established. Patients should be educated for lifestyle changes such as weight control, increased physical exercise, and smoking cessation, which are potentially beneficial in preventing diabetes mellitus and coronary artery disease. Furthermore, the morbidity and mortality caused by diabetes mellitus can be reduced by secondary prevention through regular screening, early detection, and appropriate treatment of chronic complications. In many developing countries in Asia, the limited health care resources must be rationally allocated to programmes of proven efficacy. This is a tough challenge indeed, and the decisions made will influence the quality of diabetes care in Asia. References 1. King H, Auburt RE, Herman WH. Diabetes Care. 1998; 21:1414-31. 2. Ramachandran A, Snehalatha C, Viswanathan V. Current Science 2002; 83:12:1472-76. 3. Ramachandran A. Socioeconomic burden of diabetes in India. Suppl. JAPI 2007; 55:9 4. Mohan V, Sandeep S, Deepa R. Indian scenario. Indian J Med Res 2007; 125:225-30. 5. Leung GM, Lam K. HKMJ 2000; 6:61-68. 6. Rema M, Pradeepa R. Indian Med J Res 2007; 125:297-310. 7. American diabetic association. Nephropathy in diabetes: Diabetes Care. 2004; 27:S79-83. 8. Chowdhary TA, Lasker SS. Q J Med 2002; 95:241-46. 9. Deepa R, Mohan V. Current Science 2002; 83:12:1497-1505. 10. Harney F. Medicine 2006; 34:3:95-98. 11. Gupta R, Rastogi P, Sarna M, Sharma SK. JAPI 2007; 55:621-627. 12. Haffner SM, Lehto S, Laakso M. N Engl J Med 1998; 330:229. 13. Beach KW, Bedford GR. Diabetes Care. 1998; 11:464-72. 14. Kannel WB. Drugs Ageing. 2003; 20:277-86. 15. Stamler J. 1991; 18:I95-I107. 16. Groot M, Anderson R, Kenneth E. Psychosomatic Medicine 2001; 63:619-30. 17. Ofra KL, Murad H, Raz I. Diabetes Care. 2005; 28:1739-44. 18. Ruwaared D, Annemieke MW, Coen DA. Diabetes Care 2003; 26:2604-08. 19. Selvin E, Coresh J, Frederick LB. Diabetes Care 2006; 29:2415-19. 20. Arauz-Pacheco C, Parrott MA, Raskin P. Diabetes Care. 2004; 27:S65-S7. 21. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, et al. N Engl J Med. 1996; 334:13-8. 22. Integrated community-based prevention of major noncommunicable disease in SEAR-Report of an informal consultation, WHO SEARO, New Delhi, India 2003; 27-31. 23. King H, Kriska AM. Diabetes Care 1992; 15:4:1794.