The Hypertension Diabetes Continuum

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1 HIGHLIGHTED MEETINGS SERIES The Hypertension Diabetes Continuum Bernard M. Y. Cheung, PhD, FRCP Abstract: Hypertension and type 2 diabetes are both common chronic conditions that affect a major proportion of the general population. They tend to occur in the same individual, suggesting common predisposing factors, which can be genetic or environmental. Although the genes causing hypertension or diabetes await elucidation, the environmental causes of these diseases are well known. Obesity and physical activity are the 2 leading factors that predispose to both diseases. Individuals with abdominal obesity are likely to develop lipid abnormalities and elevation of blood pressure and glucose. In time, hypertension and diabetes ensue. Because of the shared etiology, there is substantial overlap between hypertension and diabetes. In the Hong Kong Cardiovascular Risk Factor Prevalence Study, 40% of the subjects in the community had either raised blood pressure or raised blood glucose. Only 42% of people with diabetes had normal blood pressure and only 56% of people with hypertension had normal glucose tolerance. The presence of hypertension or diabetes should alert the clinician to the possibility of the other condition. Obesity, lipid abnormalities, raised blood pressure, and glucose are all components of the metabolic syndrome. The syndrome therefore implies a pathologic process, which is potentially reversible in the early stages. Previous efforts targeting smoking, hypertension, and hypercholesterolemia have started to bear fruit. However, obesity is on the increase in developed and developing countries. It is now time to focus on obesity and the metabolic syndrome, which require more a public health than a pharmacologic approach. Key Words: blood pressure, blood glucose, hypertension, diabetes, dysglycemia, obesity, metabolic syndrome (J Cardiovasc Pharmacol TM 2010;55: ) THE HYPERTENSION DIABETES CONTINUUM Hypertension and type 2 diabetes are both common chronic conditions that affect a major proportion of the general population. In the United States, approximately 29.3% and 7.8% of the general population have hypertension or diabetes, respectively. 1,2 If there is no association between the 2 diseases, then one would expect 29.3% of people with diabetes to have hypertension and 7.8% of people with hypertension to have diabetes. In reality, hypertension and diabetes are found in the same individual more often than would occur by chance. Received for publication November 1, 2009; accepted November 20, From the Department of Medicine, University of Hong Kong, Hong Kong. The authors report no conflicts of interest. Reprints: Professor Bernard M. Y. Cheung, PhD, FRCP, University Department of Medicine, Queen Mary Hospital, Hong Kong ( mycheung@hku.hk). Copyright Ó 2010 by Lippincott Williams & Wilkins This suggests either shared genetic or environmental factors in the etiology. Not much can be said about shared genetic factors because the genetics of the 2 diseases, hypertension and diabetes, have not been well worked out. Genome scans involving thousands of subjects and controls have revealed a large number of genes with small effects, as opposed to a small number of genes with large effects anticipated originally. 3,4 There is little overlap in the candidate genes for hypertension and diabetes identified so far. Observational studies, studies of twins, and clinical experience all suggest that hypertension and diabetes run in families. 5 Although this may be due to shared environment and lifestyle, a genetic basis is also possible, although the lack of common susceptibility genes with large effects means that the disease-causing genes might be different in different families. In contrast, the environmental factors leading to hypertension and diabetes are well known. Obesity, high salt diet, diet high in saturated fats and low in fruits and vegetables, stress, physical inactivity, tobacco smoking, alcohol in excess, and certain medications are known risk factors for the development of hypertension. 6 The leading factors causing type 2 diabetes include obesity, inappropriate diet, physical inactivity, pregnancy, and some medications such as corticosteroids. Obesity and physical inactivity are therefore common factors in the etiology of hypertension and diabetes. Hypertension and diabetes are both components of the metabolic syndrome. 7 The syndrome is defined by a number of features, including obesity, dyslipidemia [raised triglycerides and reduced high density lipoprotein (HDL) cholesterol], high blood glucose, and high blood pressure (Table 1). Abdominal or central obesity is a key component of the syndrome. The prevalence of the metabolic syndrome in the United States is 34% in men and 35% in women. 8,9 Its prevalence increases with age and exceeds 40% in the elderly. Although the metabolic syndrome has been defined relatively recently, it is important because it predicts cardiovascular disease and the development of diabetes. 10 It has been shown to predict the development of hypertension also. 11 The components of the metabolic syndrome are not and need not all be present at the same time. Indeed, abdominal obesity commonly precedes dyslipidemia, with hypertension and diabetes developing later Thus, obesity is often the precursor condition, which means that losing weight might be a practicable measure to prevent the development of the metabolic syndrome, hypertension and diabetes Obesity raises blood pressure by many mechanisms. 6,16,17 In an obese person, the cardiac output rises in proportion to the level of oxygen and perfusion requirements. In someone with abdominal obesity, the rise in blood pressure J Cardiovasc Pharmacol ä Volume 55, Number 4, April

2 Cheung J Cardiovasc Pharmacol ä Volume 55, Number 4, April 2010 TABLE 1. The New Definition of the Metabolic Syndrome 7 3 or More of the Following Waist circumference Population- and country-specific definitions 7 pressure $130/85 mm Hg or on treatment Plasma triglyceride $150 mg/dl (1.7 mmol/l) or on specific treatment Plasma HDL,40 mg/dl (1.0 mmol/l) in men,50 mg/dl (1.3 mmol/l) in women or on specific treatment FPG $100 mg/dl (5.6 mmol/l) or on specific treatment can also be due to increased peripheral vascular resistance. 6 This increase may be related to activation of the sympathetic nervous system and the renin angiotensin system. High leptin levels found in obesity may activate the pro-opiomelanocortin pathway and the sympathetic nervous system. 16 The renin angiotensin system is activated by a number of pathways, including the secretion of angiotensinogen and aldosteronereleasing factors by adipose tissue. 17 Activation of the sympathetic nervous system and the renin angiotensin system, compression of glomeruli and decreased response to natriuretic peptides, result in sodium retention and shift of the pressure natriuresis curve. 6 Over a long period of time, structural changes occur in the kidney, including hyaline deposition and glomerulosclerosis. When the renal function starts to decline, a vicious cycle occurs. Age is also a common factor underlying the development of hypertension and diabetes. Both conditions tend to develop in later life and their prevalence is quite high in the elderly. In the adult population in Hong Kong, about 20%, 9.6%, and 12.5% of adults have hypertension, diabetes, and the metabolic syndrome, respectively Among the elderly in Hong Kong, roughly half are hypertensive and up to one-third may have diabetes. Although age is not modifiable, obesity is potentially reversible. It has emerged as the precursor of both hypertension and diabetes in Hong Kong. 18,19 Besides people having both hypertension and diabetes, there are also many people with hypertension who have prediabetes, and conversely, many people with diabetes who have prehypertension. The association between raised blood pressure and dysglycemia was therefore investigated in the Hong Kong Cardiovascular Risk Factor Prevalence Study Cohort. 20 The Hong Kong Cardiovascular Risk Factor Prevalence Study started in 1995 when 2895 Chinese adults (1412 men and 1483 women, aged 25 74) were recruited from the general population in Hong Kong through random telephone numbers. 21 In , 1944 of these subjects underwent a detailed examination in a follow up study, the Hong Kong Cardiovascular Risk Factor Prevalence Study In this study, blood pressure was measured three times in resting subjects. A subject was classified hypertensive if the systolic blood pressure (SBP) $ 140 mm Hg, or the diastolic blood pressure (DBP) $ 90 mm Hg, or if the subject had previously been diagnosed to have hypertension and was taking antihypertensive medications. Optimal (SBP, 120 mm Hg and DBP, 80 mm Hg), normal (SBP mm Hg and/or DBP mm Hg), and high-normal (SBP mm Hg and/or DBP mm Hg) blood pressure were defined according to European Society of Hypertension and the European Society of Cardiology criteria. 22 In the study, raised blood pressure included highnormal blood pressure and hypertension. Diabetes was defined as a fasting plasma glucose (FPG) concentration $7.0 mmol/l (126 mg/dl), or if the 2-hour plasma glucose concentration in an oral glucose tolerance test (OGTT) $11.1 mmol/l (200 mg/dl), or if the subject had been diagnosed to have diabetes previously and was receiving medications for diabetes. 23 Impaired fasting glucose (IFG) was defined as an FPG of mmol/l ( mg/dl). Impaired glucose tolerance (IGT) was defined as an FPG,7.0 mmol/l (126 mg/dl) and a 2-hour OGTT plasma glucose concentration $7.8 (140 mg/dl) and,11.1 mmol/l (200 mg/dl). In this study, dysglycemia included IGT, IFG, and diabetes. The characteristics of subjects with normal glucose tolerance (NGT), IGT, IFG, and diabetes are shown in Tables 2A and B. As expected, IGT, IFG, and diabetes were related to age, body mass index, waist circumference, waist-to-hip ratio, blood pressure, and blood glucose. Raised homeostasis model assessment of insulin resistance (HOMA-IR) 24 and fasting insulin were observed in men with IGT, IFG, and diabetes but only in women with diabetes. Men and women with diabetes had lower HDL and higher triglyceride levels. There were 91 men and 135 women with purely IGT, and only 25 men and 16 women with IFG (including people with both IFG and IGT). IFG in Hong Kong Chinese without diabetes was therefore relatively uncommon. In contrast, there were more people with IGT than diabetes. Table 2 also shows the characteristics of the subjects according to whether they have optimal, normal, high-normal blood pressures, or hypertension. High-normal blood pressure and hypertension were related to age, waist circumference, waist-to-hip ratio, fasting, and OGTT 2-hour blood glucose, HOMA-IR, total cholesterol, and triglycerides. Low-density lipoprotein (LDL) cholesterol was higher in people with hypertension. The level of HDL was lower in women with hypertension. In people with hypertension, there were significant abnormalities in glucose metabolism and triglycerides. In multivariate analysis, body mass index, fasting glucose, and triglycerides were independent predictors of the development of diabetes (Table 3). Age, systolic blood pressure, and triglycerides were independent predictors of the development of hypertension. The independent predictors of the development of diabetes and hypertension together were body mass index, systolic blood pressure, and OGTT 2-hour glucose. If 2-hour glucose was excluded as a predictor variable, as it might not always be available, then the independent predictors were body mass index, systolic blood pressure, and triglycerides. Figure 1A shows the proportion of subjects with diabetes, hypertension, both, or neither. Among 1862 subjects, 77.4% had neither diabetes nor hypertension. 4.8% had diabetes only, 13.7% had hypertension only, and 4.1% had both conditions. 46.4% of people with diabetes also had hypertension, whereas 23.2% of people with hypertension q 2010 Lippincott Williams & Wilkins

3 J Cardiovasc Pharmacol ä Volume 55, Number 4, April 2010 Hypertension and Diabetes TABLE 2. Baseline Characteristics of Subjects (n = 1862) According to Glycemic and Status Total NGT IGT IFG* Diabetes Optimal Normal High-Normal Hypertensive A. Men Number Age (yrs) c b c c c Diabetes in either parent (%) Hypertension in c either parent (%) Body mass index (kg/m 2 ) c c c Waist circumference c c a c c (cm) Waist-to-hip ratio c b c c c Systolic blood c c c c c c pressure (mm Hg) Diastolic blood c c c c c c pressure (mm Hg) Fasting glucose c c b c OGTT 2-hour glucose c c c b c HOMA-IR 1.1 ( ) 1.0 ( ) 1.3 ( ) c 1.8 ( ) c 2.2 ( ) c 1.0 ( ) 1.1 ( ) 1.2 ( ) b 1.6 ( ) c Fasting insulin (miu/l) 4.7 ( ) 4.4 ( ) 5.9 ( ) c 6.3 ( ) a 5.7 ( ) c 4.3 ( ) 4.7 ( ) 4.9 ( ) b 6.5 ( ) c Total cholesterol b b c LDL b c HDL c Triglycerides a c c c Tobacco use Regular alcohol consumption Physically active B. Women Number Age (yrs) c b c c c c Diabetes in either parent (%) Hypertension in either parent (%) Body mass index (kg/m 2 ) c c c c c c Waist circumference c c c c c c (cm) Waist-to-hip ratio c c c c c c Systolic blood c c c c c pressure (mm Hg) Diastolic blood c c c c c pressure (mmhg) Fasting glucose b c c a c c OGTT 2-hour glucose c c c a b c HOMA-IR 1.2 ( ) 1.0 ( ) 1.5 ( ) 2.0 ( ) 2.7 ( ) c 1.0 ( ) 1.3 ( ) 1.6 ( ) a 1.8 ( ) c Fasting insulin (miu/l) 5.2 ( ) 4.7 ( ) 6.5 ( ) 7.1 ( ) 8.0 ( ) c 4.4 ( ) 5.5 ( ) 6.8 ( ) 7.1 ( ) c (continued on next page) q 2010 Lippincott Williams & Wilkins 335

4 Cheung J Cardiovasc Pharmacol ä Volume 55, Number 4, April 2010 TABLE 2. (continued) Baseline Characteristics of Subjects (n = 1862) According to Glycemic and Status Optimal Normal High-Normal Hypertensive Total NGT IGT IFG* Diabetes Total cholesterol c b c c c c LDL c b c b c c HDL c c c Triglycerides c a c b c c Tobacco use Regular alcohol consumption Physically active Data are shown as mean 6 SD, median (interquartile range) or percentages. Dunnett ttest or chi-square test was used as appropriate. a P, 0.05; b P, 0.01; c P, compared with NGT or optimal blood pressure. *Includes those with both IFG and IGT. Ever been a smoker. At least once a week. Taking exercise at least once a week in the past month. To convert mmol/l to mg/dl, divide by for glucose, for cholesterol, and for triglycerides. also had diabetes. Figure 1B shows the proportion of subjects with raised blood pressure, dysglycemia, both, or neither. Only 59.7% of subjects in the study had NGT and normal blood pressure, 11.4% had both raised blood pressure and dysglycemia, 17.1% have raised blood pressure only, and 11.8% have dysglycemia only. Only 42% of people with diabetes had normal or optimal blood pressure; 46% were hypertensive and 12% had highnormal blood pressure. Only 56% of people with hypertension had NGT; 24% had diabetes and 20% had IGT. The overlap between hypertension and diabetes is an important clinical question. Among the different components of the metabolic syndrome, 7 hypertension, and diabetes are particularly important because they are common and when untreated, can lead to serious complications. Effective treatments, albeit not cures, are available for these diseases that reduce morbidity and mortality. For central obesity, low HDL, and hypertriglyceridemia, the treatment in the first instance includes therapeutic lifestyle changes, such as diet and regular physical activity. The overlap between diabetes and hypertension is substantial, but it becomes more so if one considers dysglycemia and raised blood pressure. More than half of people with diabetes have raised blood pressure and about half of people with hypertension have dysglycemia. In the crosssectional analysis (Table 2), the characteristics of people with diabetes and hypertension showed many similarities. Both diabetes and hypertension were associated with age, male sex, obesity, blood pressure, glucose, and triglycerides. This clustering of risk factors reaffirms the metabolic syndrome as an important underlying factor in cardiometabolic disease in Hong Kong Chinese. 25,26 Furthermore, the prospective analysis showed that these factors predicted the development of diabetes and hypertension. If diabetes and hypertension share similar etiologic factors, it would of interest to find out if there are factors that TABLE 3. Baseline Predictors of the Development of Hypertension, Diabetes, or Both Over a Median of 6.4 Years of Follow-Up Development of Diabetes Only (Cases = 56, N = 1293) Development of Hypertension Only (Cases = 153, N = 1242) Development of Diabetes and Hypertension (Cases = 25, N = 1242) Development of Diabetes and Hypertension (Cases = 29, N = 1293)* Predictor Hazard Ratio (95% CI) P Hazard Ratio (95% CI) P Hazard Ratio (95% CI) P Hazard Ratio (95% CI) P Age, per year 1.05 ( ),0.001 Body mass index, per kg/m 2 Systolic blood pressure, per mmhg 1.07 ( ), ( ) ( ) Fasting glucose, per mmol/l 6.22 ( ),0.001 OGTT 2-hour glucose, per mmol/l 2.02 ( ),0.001 Triglycerides, per mmol/l 1.74 ( ), ( ) ( ) Stepwise (forward) Cox proportional hazards model was used. Age, gender, smoking were entered into the model. Other variables were included if P, Subjects with missing data were excluded. *OGTT 2-hour glucose was excluded as a predictor variable q 2010 Lippincott Williams & Wilkins

5 J Cardiovasc Pharmacol ä Volume 55, Number 4, April 2010 Hypertension and Diabetes FIGURE 1. Pie chart showing the percentage of subjects (n = 1862) with diabetes and hypertension (A), and the percentage with dysglycemia and raised blood pressure (B). BP, blood pressure. could distinguish between those who would develop one or the other. We found that the baseline blood pressure predicted the development of hypertension and also the development of diabetes and hypertension together. Interestingly, the 2-hour glucose concentration in an OGTT was better than the baseline fasting glucose in predicting the development of diabetes and hypertension together. However, it may not be feasible to perform OGTTs in routine clinical settings. Although it is hoped that IFG may identify the group of people with prediabetes, in Hong Kong Chinese at least, the IGT seems to pick out a larger number of subjects. We have previously shown in long-term follow-up that the conversion from IGT to diabetes is considerable, 18 such that the risk of developing diabetes is too overwhelming to be overlooked. Our group has also shown that IGT and IFG identify different groups of people with different characteristics. 27 Future guidelines may have to address the issue of the use of OGTT in populations in which the risk of developing diabetes is high. In multivariate analysis, family history of diabetes or hypertension was not a significant independent predictor of either condition. Nevertheless, in previous studies of single nucleotide polymorphisms (SNPs) in this cohort, we found that SNPs that predict the development of diabetes also predicted the development of hypertension In genome scans in Hong Kong Chinese, the region associated with diabetes was also associated with the metabolic syndrome, which includes hypertension as a component. 32,33 The common etiologic factors suggest that the common forms of diabetes and hypertension may be part of a continuum, and that they are different manifestations of the metabolic syndrome, the key cause of which is obesity. Rather than viewing hypertension and diabetes as risk factors or precursors for diseases like myocardial infarction, stroke, and renal failure, the time has come for hypertension and diabetes to be seen as complications of obesity and the metabolic syndrome. As such, hypertension and diabetes are in many cases preventable. Thus, a new paradigm is needed in the management of patients with diabetes and hypertension. Patients with diabetes need to be investigated and managed for hypertension or prehypertension and conversely, patients with hypertension need to be screened, ideally with an OGTT, for diabetes or prediabetes. A new model may be needed for the delivery of care to patients with type 2 diabetes, hypertension, or both. The optimal treatment of diabetes and hypertension require long-term, regular, and careful follow-up. There is a wealth of data to show that good control of diabetes and hypertension result in substantially better long term outcome. 34,35 Our results should help to inform the planning of delivery of care to patients with diabetes and hypertension, and those who have both conditions. Triglycerides emerged as an independent predictor of diabetes, hypertension, or both in our analysis. This is consistent with our previous observations. 12 Hypertriglyceridemia is a common lipid abnormality in diabetes, but it is not a well-recognized abnormality in hypertension. The fact that it predicts the development of hypertension shows that hypertension is not just a vascular disease but is also associated with multiple metabolic abnormalities. 26,36 The circulating triglyceride concentration is related to adiposity and is increased in insulin resistance and glycemia. 37 In Hong Kong, an SNP in the apolipoprotein A5 gene is associated with higher plasma triglyceride concentrations. 38 This is a remarkable example of a common polymorphism having a major impact on a biochemical parameter. Apart from susceptibility to coronary heart disease, diabetes and hypertension, obesity, and the metabolic syndrome is also associated with many of the most common diseases in the community. These include a 9-fold risk of sleep apnea, 39 a 5-fold risk of chronic renal failure, 40 a 3-fold risk of nonalcoholic fatty liver disease, 41 a 6-fold risk of colorectal cancer, 42 and a 3-fold risk of carcinoma of the breast 43 and uterus. 44 The metabolic syndrome is not a benign condition and increases mortality. 45,46 The metabolic syndrome needs attention, just as a breast lump or a colonic polyp cannot be left until it turns malignant. There is cause for optimism, however. In the United States, blood pressure and cholesterol have been falling for over a decade, 11,47,48 suggesting that it is possible, through concerted efforts, to change these parameters in the whole significant decreases in heart attacks and strokes in the United States. Unfortunately, although the treatment of diabetes is q 2010 Lippincott Williams & Wilkins 337

6 Cheung J Cardiovasc Pharmacol ä Volume 55, Number 4, April 2010 improving, 49 there is an increase in obesity, the metabolic syndrome, and diabetes. 8 Combating obesity and the metabolic syndrome should therefore require the same magnitude of resources as those that have gone into the control of smoking, hypertension, and hypercholesterolemia. In conclusion, there is substantial overlap between diabetes and hypertension, which is greater if one considers raised blood pressure and dysglycemia. Diabetes and hypertension share common etiologic factors related to obesity and the metabolic syndrome. For patients with diabetes or hypertension, the precursor of the other condition should be detected and therapeutic lifestyle changes considered. Overlap between the 2 conditions may be a double whammy for the untreated patient, but it also offers the opportunity to prevent 2 diseases simultaneously through adoption of healthy lifestyle changes. ACKNOWLEDGMENTS The Hong Kong Cardiovascular Risk Factor Prevalence Study Steering Committee consisted of E. D. Janus (Chairman), C. S. Cockram, R. Fielding, A. J. Hedley, P. Ho, C. P. Lau, M. Lo, S. L. Lo, P. L. Ma, J. R. C. Maserei, Y. T. Tai, B. Tomlinson, S. P. Wong, and J. L. F. Woo. The Hong Kong Cardiovascular Risk Factor Prevalence Study was supported by the Hong Kong Research Grants Council (#407/94M, #7229/01M, and #7626/07M), Hong Kong Health Services Research Committee (# and #411026), Sun Chieh Yeh Heart Foundation, and Hong Kong Society for the Aged. The author wishes to thank S.F. Chung, T.J.T. Cheung, R.W.Y. Lam, R.Y.H. Leung, S.C.H. Wong, S.T.S. Siu, G. Cheung, J.L.F. Lo, D.F.Y. Chau, C.Y. Law, Y.B. Man, and the late M.R. Janus. REFERENCES 1. Ong KL, Cheung BMY, Man YB, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults Hypertension. 2007;49: Ong KL, Cheung BMY, Wong LYF, et al. 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7 J Cardiovasc Pharmacol ä Volume 55, Number 4, April 2010 Hypertension and Diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009; 373: Verdecchia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet. 2009;374: Reaven G. Metabolic syndrome: pathophysiology and implications for management of cardiovascular disease. Circulation. 2002;106: Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176: Cheung BMY, Ong KL, Tso AWK, et al. A meta-analysis of studies of the effect of apolipoprotein A5-1131T.C polymorphism on triglyceride level in Chinese. Proceedings of the British Pharmacological Society at: Accessed February 8, Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev. 2005;9: Lucove J, Vupputuri S, Heiss G, et al. Metabolic syndrome and the development of CKD in American Indians: the Strong Heart Study. Am J Kidney Dis. 2008;51: Abdeen MB, Chowdhury NA, Hayden MR, et al. Nonalcoholic steatohepatitis and the cardiometabolic syndrome. J Cardiometab Syndr. 2006;1: Chan AO, Jim MH, Lam KF, et al. Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease. JAMA. 2007;298: Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr. 2007;86:S823 S Cust AE, Kaaks R, Friedenreich C, et al. Metabolic syndrome, plasma lipid, lipoprotein and glucose levels, and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer. 2007;14: Isomaa B Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001; 24: Thomas GN, Schooling CM, McGhee SM, et al. Metabolic syndrome increases all-cause and vascular mortality: the Hong Kong Cardiovascular Risk Factor Study. Clin Endocrinol. 2007;66: Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, N Engl J Med. 2007;356: Li M, Ong KL, Tse HF, et al. Utilization of lipid lowering medications among adults in the United States Atherosclerosis. 2010;208: Cheung BMY, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to Am J Med. 2009;122: q 2010 Lippincott Williams & Wilkins 339