If you’re among the close to 21 million Americans that have diabetes, even minor or ordinary diabetes for years or have been recently diagnosed, be sure to …
REVIEW
AMELIORATION OF HYPERTENSION IN PATIENTS WITH TYPE 2 DIABETES
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William B White, MD
ABSTRACT
Diabetes and hypertension are 2 of the most potent risk factors for the development of cardiovascular disease, and they rarely exist in isolation In fact, hypertension and diabetes are inextricably linked–most patients with diabetes have hypertension and a significant proportion of hypertensive patients become diabetic If we are to prevent the link between developing hypertension and type 2 diabetes, it is necessary to understand how hypertension, diabetes, and excess weight are related This article reviews the pathophysiologic mechanisms involved in patients with hypertension and diabetes, and how they invoke a complex interplay among the reninangiotensin-aldosterone system, the sympathetic nervous system, the endothelium, the kidneys, and glucose metabolism The current guidelines for preventing and managing hypertension in patients with type 2 diabetes are also briefly reviewed In recent years, we have learned that hypertension can be prevented or effectively managed in patients with type 2 diabetes, utilizing the detailed recommendations from several established professional
organizations to the wide range of currently available drugs Our increasing understanding of the complex pathophysiology highlights why it is imperative that we must aggressively manage blood pressure in patients with type 2 diabetes
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INTRODUCTION Diabetes and hypertension are 2 of the most wellknown and potent risk factors for cardiovascular disease CVD development, and they rarely exist in isolation Hypertension is a highly prevalent condition among the general population, affecting 1 in 3 adult Americans In fact, the lifetime risk of developing hypertension is greater than 901 The rapidly increasing prevalence of type 2 diabetes in the United States is well known2 A record 7 of the US population has diabetes, including 96 of the US adult population ie, 20 years3 In tandem with this explosion of type 2 diabetes is the rapidly increasing proportion of the US population who are aging and developing chronic disease Moreover, the metabolic syndrome– the constellation of cardiovascular and physical changes that are often the precursor to type 2 diabetes–is also at record high levels 1 in 3 Americans between the ages of 50 and 59 years has metabolic
syndrome4 The prevalence of metabolic syndrome increases with age, reaching 44 for those 60 to 69 years5 Hypertension in patients with diabetes is common, but there are important differences between hypertension in type 1 versus type 2 diabetes Most patients with type 2 diabetes have essential hypertension, whereas patients with type 1 diabetes often have hypertension secondary to nephropathy6,7 However, nephropathy is both a cause and consequence of hypertension, creating an unfavorable prognosis for patients with diabetes In fact, diabetes is now the leading cause of chronic kidney disease CKD leading to dialysis in the United States As hypertension and type 2 diabetes are frequent comorbidities, it is necessary to understand how they are related and how important it is to maintain optimal blood pressures in patients with diabetes
Professor of Medicine, Chief, Hypertension and Clinical Pharmacology, The Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, Connecticut Address correspondence to: William B White, MD, Professor of Medicine, Chief, Hypertension and Clinical Pharmacology, The Pat and Jim Calhoun Cardiology Center, University of
Connecticut Health Center, Farmington, CT 06030 E-mail: wwhite@nso1uchcedu
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THE PATHOPHYSIOLOGY OF HYPERTENSION AND DIABETES Patients with diabetes are at increased risk of hypertension and as many as 80 of patients with type 2 diabetes will die of macrovascular disease Nonetheless, not all hypertensive patients will develop hyperinsulinemia, and not all hyperinsulinemic patients develop hypertension Hypertension and glucose intolerance are part of the metabolic syndrome Each of the components of the metabolic syndrome are independent risk factors for CVD and CKD, and their effects as risk factors are additive when present at the same time6,8 Ultimately, hypertension leads to end-organ damage in the kidney, heart, and brain Figure 19 In the presence of diabetes, these pathophysiologic effects are accelerated Hypertension in patients with type 2 diabetes results from a complex pathophysiologic interplay that includes the renin-angiotensin-aldosterone system RAAS, the sympathetic nervous system, the endothelium, the kidneys, and glucose metabolism, along with other mechanisms that are under investigation eg, left ventricular
hypertrophy, cardiac hyperreactivity, dyslipidemia, and cell membrane ion exchange6 ACTIVATION OF RAAS AND SYMPATHETIC NERVOUS SYSTEM The RAAS is a pathophysiologic cornerstone in the hypertensive disease process Renin is an enzyme that cleaves angiotensinogen to produce an inactive peptide angiotensin I, which is converted by the angiotensinconverting enzyme ACE and other enzyme systems to angiotensin II, a potent vasoconstrictor10 In addition to its well-known effects on vascular resistance, angiotensin II also induces cell growth in the arterial wall and cardiac myocyte and increases oxidative stress; it is also proinflammatory and thrombogenic Angiotensin-converting enzyme also inactivates bradykinin, a peptide that stimulates the release of nitric oxide, which counteracts the effects of angiotensin II by promoting vascular smooth muscle relaxation Thus, ACE inhibitors have 2 effects– reducing the production of angiotensin II and preserving bradykinin, which has biological actions that oppose those of angiotensin The RAAS is controlled by the sympathetic nervous system SNS, which is activated by many factors associated with type 2 diabetes, including hyperinsu-
linemia,
excess weight, and an unhealthy diet The Normative Aging study, involving a population-based cohort followed in Boston, found that SNS activity was elevated with hyperinsulinemia and that activation also correlated with body mass index BMI11 Numerous investigators have shown that obese subjects have elevated SNS activity, measured both directly and indirectly6,12-14 Both human and animal studies have shown that food intake primarily fat and carbohydrates increases SNS activity, whereas fasting and weight loss decrease the activity6,15,16 Insulin is believed to partially mediate the effect of diet by stimulating glucose uptake and metabolism and ultimately disinhibiting sympathetic neurotransmission from the brain stem6,17 Several investigators have found that numerous other mechanisms and mediators are thought to cause SNS activation in the insulin-resistant state, including renal afferent nerve stimulation by increased intrarenal pressure, plasma free fatty
Figure 1 The Pathophysiologic Sequelae of Hypertension:Target Organ Damage
Prehypertension Asymptomatic Established hypertension
Target organ disease
Oligosymptomatic
Proteinuria Nephrosclerosis
Left-ventricular
hypertrophy
Retinopathy Binswanger lesions
Symptomatic
Chronic renal failure
Coronary artery disease Angina
Systolic/ diastolic dysfunction
Atrial fibrillation Ventricular arrhythmias
Dementia Transient ischemic attack
Polysymptomatic or end-stage disease
End-stage renal disease
Myocardial infarction
Congestive heart failure
Ventricular tachycardia Ventricular fibrillation
Stroke
Death
Reprinted with permission from Messerli et al Lancet 2007;370:591-6039
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acids, and angiotensin II6,12-14,16 The RAAS has been shown to play an important role in insulin sensitivity Two large trials of ACE inhibitors Heart Outcomes Prevention Evaluation and Captopril Prevention Project showed that this class of drugs decreased the risk of developing type 2 diabetes in patients with hypertension and/or vascular diseases18,19 ENDOTHELIAL DYSFUNCTION AND INFLAMMATION The endothelium has been described as the organ that bridges several cardiovascular risk factors eg, hypertension, dyslipidemia, smoking, diabetes, and congestive heart failure and may be the crystallizing nucleus for the development of vascular inflammation and atherosclerosis20-23
The endothelium is responsible for maintaining the balance between vasoconstriction and vasodilation by producing compounds that regulate vascular homeostasis, among them angiotensin II and nitric oxide The endothelium also helps to maintain normal blood viscosity by balancing clotting factors24 Endothelial dysfunction involves impaired vasomotor response reduced vasodilation and increased endothelium-dependent contraction, cell proliferation, platelet adhesion/aggregation, vascular permeability, and vascular inflammation by stimulating production of adhesion molecules, growth factors, and vasoconstricting agents20,23,25 Nitric oxide is a vasodilator Reactive oxygen species, created during inflammation, impair vascular relaxation by reducing nitric oxide and increasing vascular contractile responses6,26 Activation of the RAAS also leads to endothelial dysfunction and inflammation by promoting production of angiotensin II, which induces vascular injury through several mechanisms, including vasoconstriction, cell growth, oxidative stress, and inflammation inducing release of cytokines and proinflammatory transcription factors, all of which contribute to the prothrombotic state and
plaque buildup and instability, and ultimately plaque rupture20,27,28 Angiotensin II is also one of the main mediators of the RAAS system, thus it is a continuous feedback loop Hypertension and insulin resistance contribute to endothelial dysfunction and inflammation in the vascular wall as well as smooth muscle cell proliferation, extracellular matrix deposition, cell adhesion, and thrombus formation, all processes that lead to atherosclerosis20 Thus, the relationship between RAAS, endothelial dysfunction, and hypertension magnifies pathophysiologic risk in which continued promotion
of endothelial dysfunction increases hypertension and elevated vascular resistance, and the activation of the RAAS exacerbates endothelial dysfunction RISK FACTORS AND RISK STRATIFICATION FOR CARDIOVASCULAR DISEASE Diabetes is the most impactful risk factor for CVD, followed by systolic blood pressure, smoking, and dyslipidemia Most importantly, hypertension is one of the most modifiable risk factors for chronic heart disease, stroke, congestive heart failure, end-stage renal disease, and peripheral vascular disease1 Data from the National Health and Nutrition Examination Survey NHANES have shown that
more than 66 of the US adult population is now overweight or obese and the prevalence is rising at an alarming rate29 The Centers for Disease Control and Prevention reports that in 2006, only 4 states had a prevalence of obesity less than 20 Twenty-two states had a prevalence of obesity equal or greater than 25; 2 of these states Mississippi and West Virginia had a prevalence of obesity equal to or greater than 3030 The vast majority of patients with type 2 diabetes are overweight or obese Besides increased work demanded of the heart, obesity is associated with activation of the RAAS, endothelial dysfunction, and renal dysfunction31 Moreover, the NHANES data also showed that there is a direct linear relationship between BMI and systolic and diastolic blood pressure32 In addition, a shortterm study of 25 obese patients showed that with weight loss came significant reductions in plasma renin activity, aldosterone, and mean arterial pressure6,13 However, not all forms of obesity are created equal Visceral adiposity, in particular, is especially harmful with respect to cardiovascular risk Visceral adipocytes are metabolically active, and visceral tissue is considered to be an endocrine
tissue6 Visceral adipocytes stimulate several pathophysiologic processes, including inflammation, hypertension, and renal injury, and they reduce thrombolysis by producing inflammatory cytokines, angiotensinogen, ACEs, and the angiotensin I receptor6 Visceral adipocytes are also insulin resistant6 Recall that the RAAS can be activated centrally by increased free fatty acids, which increase aldosterone levels in the insulin resistance state; it can also be activated by adipose tissue Angiotensin II, ACE levels, and plasma renin activity correlate with BMI6,33
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Visceral adiposity contributes to hypertension through several mechanisms, including RAAS activation, increased SNS activity, sodium retention and volume expansion, progressive CKD, and inhibition of insulin signaling5,6,14,34 Therefore, 1 important mechanism of preventing hypertension in patients with type 2 diabetes is weight control GUIDELINES FOR TREATMENT OF HYPERTENSION IN TYPE 2 DIABETES
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure continued the trend over the past few decades
toward more aggressive detection and management of hypertension A new category was created–prehypertension–in the hopes of identifying those prone to hypertension and preventing hypertension in the future As shown in Figure 2, prehypertension is defined as systolic blood pressure of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg In patients with type 2 diabetes, drug therapy is warranted to achieve a target blood pressure of lower than 130/80 mm Hg due to the progressive increases in cardiovascular and renal Figure 2 JNC-7 Classification and Management of Hypertension and risk seen at these values8,35 A joint stateRecommendations for Patients with Type 2 Diabetes ment from the American Diabetes Association ADA and the American Heart Association AHA concurs with this Yes 2-drug 2 drug Stage 2 combination combination SBP 160 mm Hg or more aggressive approach to treating for most for most DBP 100 mm Hg hypertension in patients with type 2 diaYes Yes thiazide- 2 drug betes, noting that rigorous blood pressure Stage 1 type diuretics combination SBP 140159 mm Hg or control is absolutely necessary for reducing for most for most DBP 8089 mm Hg the progression of diabetic
nephropathy to Yes None 2-drug Prehypertension end-stage renal disease Blood pressure indicated combination SBP 120139 mm Hg or should be measured at every routine visit of for most DBP 8089 mm Hg a patient with diabetes, and those found to Yes ACE or ARB Diuretic Target for T2DM SBP 130 mm Hg DBP 80 mm Hg B CCB have systolic blood pressures higher than Encouraged Normal 130 mm Hg or diastolic blood pressure SBP 120 mm Hg higher than 80 mm Hg should have their DBP 80 mm Hg blood pressure confirmed on a separate Lifestyle Rxw/o Rxw/ modification compelling compelling day36 The National Kidney Foundation indication indication has also issued guidelines for management of hypertension in patients with diabetes ACE angiotensin-converting enzyme; ARB angiotensin receptor blocker; B blocker; CCB calcium channel blocker; DBP diastolic blood pressure; JNC-7 Seventh Report of the Joint and CKD They, too, recommend a target National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; SBP blood pressure of lower than 130/80 mm systolic blood pressure; T2DM type 2 diabetes mellitus Hg in patients with diabetes and CKD Data from US Department of
Health and Human Services ; American Diabetes Association ; National Kidney Foundation stages 1 to 437
8 35 37
All 3 guidelines also share some additional recommendations with regard to therapy, discussed in detail in the article by Dr Bakris later in this monograph In brief, patients with both diabetes and hypertension should be treated with an ACE inhibitor or an angiotensin receptor blocker8,35-37 If one class is not tolerated, the other should be substituted Other drug classes that should be added to achieve blood pressure targets and reduce CVD events include blockers, thiazide diuretics, and calcium channel blockers36 In fact, multiple agents are virtually always required to achieve blood pressure targets In an analysis of several of the large hypertension clinical trials in which the goal blood pressure was lower than 135/85 mm Hg eg, patients with diabetes or renal impairment, on average, 32 medications were utilized to achieve target blood pressure38 The ADA/AHA also recommends that if ACE inhibitors, angiotensin receptor blockers ARBs, or diuretics are used, renal function and serum potassium levels should be monitored within the first 3 months
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If potassium levels are stable over a minimum of 2 visof aspirin in primary prevention of cardiovascular its, follow-up could occur every 6 months thereafter events continues to be questioned The updated guideIn addition, orthostatic measurement of blood preslines from the British Hypertension Society state that sure should be performed in people with diabetes and doctors should not focus solely on blood pressure, but hypertension when clinically indicated For patients must also formally assess total risk of CVD and use not achieving target blood pressure despite multiplemultifactorial interventions, including statins and drug therapy, it is valuable to consider referral to a aspirin, to reduce it40 The ADA/AHA statement indicates that aspirin therapy 75162 mg/d should be physician specializing in the care of patients with recommended as a primary prevention strategy in hypertension36 Currently, pharmacotherapy for prehypertension is those with diabetes at increased cardiovascular risk, not yet recommended Figure 2, and no antihypertenincluding those who are over 40 years of age or who sive medication is approved for use in prehypertenhave additional
risk factors family history of CVD, sion8,35 However, a recent study–the Trial of hypertension, smoking, dyslipidemia, or albuminPreventing Hypertension–suggests that ARBs may uria36 Yet, others have called into question its wide39 spread use in the absence of more data that address have some benefit as a preventive measure In this study, 809 patients with prehypertension were randomspecific subpopulations eg, those younger than age 50 ized to receive candesartan or placebo for 2 years, but years and older than age 70 years, especially considerthey were followed for 4 years After 2 years of study ing the known adverse events associated with aspirin, treatment, the relative risk of developing hypertension including gastrointestinal hemorrhage41 was reduced by 663 in the candesartan group compared to placebo P 001 After 4 years of follow-up 2 years of study treatment followed by 2 years of placebo for all participants, the benefits remained–a 156 reduction in relative risk for those who had originally Figure 3 Diastolic and Systolic Blood Pressures as Risk Factors for received candesartan P 00739 Therefore, Coronary Heart Disease Vary by Age other trials with antihypertensive
agents in this patient population are warranted, given these results Note that lifestyle modifications are an 124 115133 60 years integral part of all treatment recommenda083 071098 tions, for those with or without compelling indications, and are encouraged for those with 11 099121 SBP 5059 years normal blood pressure and prehypertensive 097 081116 DBP blood pressure values Lifestyle modifications for the prevention or management of hyper095 083109 tension should include weight control, 50 years 142 115174 increased physical activity, alcohol moderation, sodium reduction, and emphasis on 0 05 1 15 2 increased consumption of fresh fruits, vegetaHazard ratio 95 CI bles, and low-fat dairy products INDIVIDUALIZED RISK FACTORS As with many other conditions, recognized guidelines provide a starting point for treatment strategies, but ultimately management must be tailored based on each patients individual composite of risk For example, the use
P 001 P 05 Hazard ratio was associated with a 10-mm Hg increase in blood pressure This study evaluated 3060 men and 3479 women between 20 and 79 years of age Framingham Heart Study participants who were free of coronary heart disease and were not
on antihypertensive drug therapy at baseline The results show a gradual shift from diastolic blood pressure DBP to systolic blood pressure SBP as predictors of chronic heart disease risk with advancing age CI confidence interval Reprinted with permission from Franklin et al Circulation 2001;103:1245-124942
Age
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Although conventional risk calculators allow the clinician to determine cardiovascular risk based on parameters that are easily measured in a clinical setting systolic blood pressure, age, sex, cholesterol concentration, presence of diabetes, and smoking history, one could argue that such formal calculations are unnecessary for patients with hypertension and CVD, diabetes, or overt end-organ damage because these patients will clearly benefit from a multifactorial approach to risk reduction9 Moreover, it is important for the primary care clinician to recognize that hypertension and diabetes, although frequently comorbid, also show differences in prevalence in different populations, particularly based on age and ethnicity For example, although hypertension increases in prevalence with age, the effect of hypertension
on risk for coronary heart disease varies In younger persons, diastolic high blood pressure poses a greater risk, but the risk is almost equally distributed between systolic and diastolic blood pressure as patients enter their 50s Figure 3 By the time a person is at least 60 years old, systolic high blood pressure poses a higher risk for coronary heart disease Figure 342 In addition, although hypertension affects all ethnicities, there are some well-known disparities Analysis of the most recent NHANES database by Ong et al revealed an overall prevalence of hypertension of 29, but higher prevalence in non-Hispanic blacks 39 versus non-Hispanic whites 29 and Mexican Americans 2843 Thus, for the individual patient in the physicians office, approaches to prevention and management must be individualized based on the particular risk factors, clinical profile, and sociodemographic setting of the individual patient CONCLUSIONS There is evidence that hypertension can be prevented or ameliorated in patients with type 2 diabetes Undoubtedly, we have a wide range of currently available drugs and detailed recommendations from several established professional organizations to address this
disorder with evidence-based medicine to support our treatment choices Moreover, our depth of understanding the complex interplay among hypertension, obesity, type 2 diabetes, and renal dysfunction shows why it is impera-
tive to aggressively manage blood pressure in patients with type 2 diabetes However, if we are to prevent the link from developing between hypertension and type 2 diabetes, we have to also overcome the challenges in adherence to weight loss, dietary changes, and physical exercise A tailored approach to both prevention and treatment of hypertension is required in this high-risk population
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Poulter NR, Brown MJ, et al British Hypertension Society guidelines for hypertension management 2004 BHSIV: summary BMJ 2004;328:634-640 41 Nicolucci A, de Berardis G, Sacco M, Tognoni G Response to Buse et al [letter] Diabetes Care 2007;30:e57-e58 42 Franklin SS, Larson MG, Khan SA, et al Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study Circulation 2001;103:1245-1249 43 Ong KL, Cheung BM, Man YB, et al Prevalence, awareness, treatment, and control of hypertension among United States adults, 1999-2004 Hypertension 2007;49:69-75
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