The current epidemic of obesity that is sweeping the United States and other industrialized countries is promoting a rapid rise in the incidence of the metabolic syndrome and type 2 diabetes. Currently about 16% of adults have overt diabetes (confirmed fasting blood sugar >125 mg/dL). Historically, much attention has been paid to the separation of juvenile from adult-onset diabetes. It now seems clear that the natural history of progression of hyperglycemic disorders in the vast majority of individuals is obesity to metabolic syndrome to noninsulin-dependent diabetes to insulin-dependent diabetes. From a target organ damage or cardiovascular risk perspective, there appears to be little reason to differentiate between type 1 and type 2 diabetes because after 20–30 years of diabetes, the adverse cardiac, vascular, and renal outcomes of the two conditions are essentially identical.
The increasing prevalence of obesity, hypertension, and abnormal glucose metabolism is a major challenge to health care in industrialized societies. This brief review summarizes the mechanistic evidence and clinical studies related to the problem of hypertension in the metabolic syndrome and diabetes to allow clinicians to provide more effective and enlightened management of these common, interrelated problems.
HISTORY, DEFINITIONS, AND PREVALENCE
The Metabolic Syndrome
For many decades, it has been apparent to experienced clinicians that the prevalence of the disease cluster that includes obesity, hypertension, and glucose intolerance is greater than that predicted by chance association. Since the first systematic analyses of this disease cluster,1,2 investigators have further defined this association and described several possible underlying mechanisms of the condition that was originally called the “insulin resistance syndrome.”3–5 Today, the term “metabolic syndrome” is generally preferred over “insulin resistance,” but the two are considered to be largely synonymous.
The most concise and well-accepted current definition of the metabolic syndrome is that provided by the National Cholesterol Education Program in its third Adult Treatment Panel (ATP III) report.6 As noted in Table I, the metabolic syndrome is present if three or more of the following conditions are met: central obesity, hypertriglyceridemia, elevated fasting blood sugar, low high-density lipoprotein cholesterol, elevated blood pressure, or increased central adiposity (waist circumference >40 inches in men or >35 inches in women). Several national and international organizations have published roughly comparable definitions of the metabolic syndrome, but the ATP III diagnostic criteria are now considered to be the standard and have been adopted by the National High Blood Pressure Education Program as part of the Joint National Committee Seventh Report (JNC 7)7
|Component||Criteria (Any Three Or More Criteria)|
|Central adiposity||Waist circumference >40 inches in men or >35 inches in women|
|Hypertension||Blood pressure 130/85 mm Hg|
|Glucose intolerance||Fasting blood sugar 110 mg/dL|
|Low high-density lipoprotein cholesterol||High-density lipoprotein cholesterol <40 mg/dL in men or <50 mg/dL in women|
|Hypertriglyceridemia||Fasting triglycerides 150 mg/dL|
The metabolic syndrome is common. From the third National Health And Nutrition Examination Survey (NHANES III) database, it is now known that there is a strong positive association of the metabolic syndrome with age and increased cardiovascular risk.8,9 The age-adjusted prevalence of the metabolic syndrome is almost 24% (about 47 million US residents), with the highest rate found in Mexican Americans (32%). Overall age-adjusted prevalence is similar for men and women, with somewhat higher rates in African-American and Mexican-American women.8
PATHOGENESIS OF HYPERTENSION
Hypertension is a core feature of the conditions in the diabetic spectrum, but the mechanisms causing the elevated blood pressure change as the hyperglycemic condition evolves.
Over the years, considerable debate has arisen regarding the interrelationships among the central pathogenetic features of the metabolic syndrome.3,10–18 There is general agreement that central (or visceral) obesity is a critical common feature. Less well known are the documented associations with increased sympathetic nervous system activity. 10,19,20 Insulin resistance is almost always present and is due, at least in part, to increased fat cell mass, which causes somatic resistance to the action of insulin, increased pancreatic insulin release, and hyperinsulinemia. Plasma insulin levels have been identified as an independent cardiovascular risk factor,21 but this association is not necessarily proof of a “toxic” effect of insulin itself.
Hyperinsulinemia can directly stimulate the sympathetic nervous system,22,23 but the intrinsic actions of catecholamines are also inherently diabetogenic,10 so it is likely that a vicious cycle arises where insulin resistance is coupled with increased sympathetic nervous overactivity. A third feature of the metabolic syndrome is salt sensitivity of blood pressure.15 Both increased renal sympathetic nerve activity and the antinatriuretic effect of insulin on renal tubular sodium reabsorption24,25 promote relative volume expansion26,27 and an exaggerated blood pressure rise in response to increased dietary salt intake. In addition, there is increased vascular sympathetic responsiveness28 and endothelial dysfunction12 in the metabolic syndrome.
The mutually reinforcing interaction between salt-sensitivity and increased sympathetic nervous system activity forms a plausible pathogenetic basis for the increased blood pressure observed in the metabolic syndrome, but other systems may also be involved. Participation of the renin-angiotensin system appears to be complex in this syndrome.29,30 Increased activity of the renin-angiotensin and sympathetic nervous systems exacerbates salt sensitivity.31 Blocking the formation of angiotensin II with an angiotensin-converting enzyme (ACE) inhibitor32 or blockade of the AT-1 receptor33 usually improves blood glucose and lowers blood pressure.
The relative contributions of genes and environment in controlling sympathetic activity and insulin sensitivity are being actively investigated. Obesity and insulin resistance are partially inherited traits.14,34 When the interaction of insulin resistance and sympathetic nervous activity was studied prospectively in Japanese men, the heritability of insulin resistance was found to be greater than the heritability of high sympathetic activity.14 The rate of rise of blood pressure over a decade was much more closely related to the degree of increase in sympathetic activation that occurred, strongly suggesting an acquired environmental component of the associated hypertension.14 In the Normative Aging Study,35 increased sympathetic activity was more powerful than plasma insulin concentration in predicting the subsequent development of hypertension.35
Hemodynamically, obese individuals with the metabolic syndrome initially manifest a relatively high cardiac output, while in later stages, there appears to be a peripheral vascular adaptation that leads to an inappropriately high systemic vascular resistance.36 Effects of obesity on arterial stiffness are complex and depend on the technique used and the type of artery (central vs. peripheral) studied.37–40 At the microcirculatory level, capillary density and surface area appear to be decreased very early in the development of hypertension41 or insulin resistance,42–44 and it has been proposed that a functional or structural microcirculatory deficiency (capillary rarefaction) contributes to the pathogenesis of the metabolic syndrome.42–44
In overt diabetes, the same mechanisms described in the metabolic syndrome appear to operate with important modifications. The most important factor affecting these changes is the insidious development of diabetic renal disease, with increasing volume-dependency of blood pressure.45,46 Large artery stiffness also increases as the metabolic syndrome progresses to overt diabetes,40,47 thereby accelerating the development of systolic hypertension. With advancing renal insufficiency, there is progressive activation of the sympathetic nervous system,48–51 often associated with baroreflex dysfunction,52,53 decreased ability to “buffer” blood pressure fluctuations, and increased blood pressure variability. The direct dependency of systemic blood pressure on the renin-angiotensin-aldosterone system (RAAS) appears to diminish, and plasma renin activity appears to decrease over time in diabetics, perhaps related to alterations in cellular calcium permeability.54 At the same time, angiotensin II appears to remain a major participant in ongoing target organ damage because anti-RAAS drugs retard the progression of diabetic renal disease.55,56 In some insulin-dependent diabetics, the syndrome of hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis) is found.57
ANTIHYPERTENSIVE DRUGS AND CARDIOVASCULAR RISK REDUCTION
Blood pressure control is the most important target organ protective factor in the metabolic syndrome and diabetes, a concept that has been clearly documented in several studies that span the spectrum of glycemic and blood pressure abnormalities.58–62 In the metabolic syndrome, although each of the components has been independently associated with increased cardiovascular morbidity and mortality, the ATP III criteria per se have not been used as primary selection criteria for a large outcome study. Nevertheless, important inferences for antihypertensive therapy across the spectrum of glycemic abnormalities can be drawn from various large-scale clinical trials.
Value of Lower Blood Pressure in Disease Prevention
In the Systolic Hypertension in the Elderly Prospective Trial (SHEP),58 which first demonstrated the value of treatment of isolated systolic hypertension in the elderly, thiazide-based therapy caused twice the absolute cardiovascular risk reduction in diabetics compared with nondiabetics. In the Antihypertensive Lipid-Lowering Heart Attack Trial (ALLHAT),62 at least half the patients entered into this study had either the metabolic syndrome or early diabetes. In ALLHAT, thiazide diuretics, ACE inhibitors, and dihydropyridine calcium antagonists were equally able to reduce the incidence of the primary end point (nonfatal myocardial infarction or cardiovascular death).62 In the dihydropyridine-based Hypertension Optimal Treatment (HOT) study,59 the value of intensive blood pressure lowering in diabetics was again demonstrated; those with the lowest blood pressures (the group randomized to achieve diastolic blood pressure <80 mm Hg) fared better overall than the groups randomized to receive less intensive blood pressure lowering.
The largest and most important clinical trial yet completed in diabetes is the United Kingdom Prospective Diabetes Study (UKPDS),60 which studied the interaction of blood sugar and blood pressure control. Several important findings emanated from this study, most notably that the single most effective means by which diabetics can avoid increased cardiovascular morbidity and mortality is fastidious blood pressure control. In UKPDS, a strong log-linear association between systolic blood pressure and cardiovascular mortality was established over the range of 115–175 mm Hg, further demonstrating the benefit of tight blood pressure control.63 When the adverse outcomes were divided into macrovascular end points (coronary heart disease, stroke, and peripheral vascular disease) and microvascular end points (dementia, retinopathy, and diabetic kidney disease), blood pressure control was substantially more important than glucose control in reducing macrovascular end points, whereas both blood sugar control and blood pressure control were important in reducing microvascular complications.60,64 In this study, it appeared to be relatively unimportant which class of drugs was used; a β-blocker regimen was equivalent to a regimen based on ACE inhibitor, calcium antagonist, or diuretic.
Benefits of blood pressure lowering extend to those whose blood pressures are below 140/90 mm Hg. In the smaller Appropriate Blood Pressure Control in Diabetes (ABCD) trial,61 normotensive individuals were randomized in a 2×2 factorial design to receive intensive blood pressure control (<130 mm Hg systolic) or less-intensive control (<140 mm Hg systolic) with simultaneous randomization to either ACE inhibitor-or calcium antagonist-based therapy. At the end of the study, those with tight blood pressure control (mean systolic blood pressure of 127 mm Hg) had fewer complications than those with less tight systolic blood pressure control (mean systolic blood pressure of 138 mm Hg). ACE inhibitor and dihydropyridine calcium antagonist appeared to be equally protective in these low-risk populations regarding stroke prevention.61
Blood Pressure Lowering vs. Drug Class
The question of the relative value of blood pressure control itself vs. the relative abilities of specific drug classes to prevent target organ damage and death is a major focus of many investigators and pharmaceutical firms. It is easy to find different opinions in the literature but little in the way of properly designed head-to-head outcomes-based comparison studies. One novel approach is a meta-regression study that analyzed the relationship between blood pressure differences in available outcome studies and the overall cardiovascular benefit conferred by this difference.65 Using this approach, Staessen and associates65 concluded that the outcome benefits from antihypertensive drugs accrued almost entirely to the degree of blood pressure reduction that was achieved, not the class of drug that was used.
One misleading and often misinterpreted study regarding the value of blood pressure lowering is the Heart Outcomes Prevention Evaluation (HOPE) program.32,66 In HOPE, both nondiabetic and diabetic individuals at high risk for coronary artery disease who received an ACE inhibitor had 20%–25% fewer cardiovascular events than those who received placebo. The HOPE investigators originally suggested that these benefits were largely “independent of blood pressure lowering” because the differences in office blood pressures between the ACE inhibitor and placebo groups was only about 3/1 mm Hg. However, no attempts were made in this community-based study to standardize blood pressure measurements or perform sufficient quality-control analyses. In addition, there were insufficient numbers of readings to achieve satisfactory discriminatory power. Furthermore, an ambulatory blood pressure monitoring substudy in a small subgroup of HOPE patients with peripheral arterial disease revealed that those who received ACE inhibitor therapy had substantially lower blood pressures (10/4 mm Hg average on 24-hour ambulatory blood pressure monitoring) than those who received placebo.67 Based on worldwide prospective follow-up studies including more than 1 million adults, a decrease of 10 mm Hg systolic would be expected to reduce ischemic heart disease events by about 25%68; thus the vast preponderance of apparent benefits of ACE inhibition in HOPE may be best explained by improved blood pressure control.
Benefits of Specific Drug Classes in Established Cardiovascular Disease
Despite the weight of evidence that lowering blood pressure is the primary goal in cardiovascular disease prevention, there is substantial evidence that specific forms of target organ damage may be best treated by specific classes of antihypertensive agents and that some classes are superior to others in diabetics with renal and cardiac damage. In the setting of diabetic renal disease, ACE inhibitors and angiotensin receptor blockers slow the rate of renal deterioration. The Captopril Collaborative Study demonstrated that ACE inhibitor-based therapy was superior to conventional treatment (diuretic, adrenergic inhibitor, and sometimes vasodilator) in retarding the progression of diabetic kidney disease and proteinuria in type I diabetes.69 Subsequent studies conducted in type II diabetics with moderate to severe nephropathy have shown that angiotensin-receptor blockers confer benefit to a similar degree as that seen with ACE inhibition. Both the Renal Endpoint Reduction with Angiotensin Antagonist (RENAAL)55 and the Intervention in Diabetic Nephropathy Trial (IDNT)56 studies confirm that angiotensin receptor blockers slow the rate of renal deterioration and reduce proteinuria to a greater degree than standard therapy (which did not include an ACE inhibitor). In a lower-risk population of type 2 diabetics with relatively normal renal function, the Irbesartan for Reduction of Microalbuminuria (IRMA-2) study demonstrated that angiotensin receptor blockade therapy retarded the progression of diabetic nephropathy.70 Of importance, the IRMA-2 study demonstrated appreciable benefit only when the higher dose of irbesartan (300 mg daily compared with 150 mg daily) was used.70
In preventing the progression of cardiovascular disease in diabetic individuals, studies have demonstrated benefits of ACE inhibitors and angiotensin-receptor blockers. In an early report of the ABCD trial,71 fewer ischemic heart disease outcomes were observed with an ACE inhibitor than with a dihydropyridine calcium antagonist. In individuals with left ventricular hypertrophy, the Losartan Intervention for Endpoint Reduction (LIFE) study72,73 demonstrated that an angiotensin receptor blocker-based regimen was superior to a β blocker-based treatment program for reducing cardiovascular disease end points (especially stroke) in diabetic and nondiabetic individuals, despite similar reductions in cuff blood pressures with the two classes of drugs.
CURRENT THERAPEUTIC RECOMMENDATIONS
Effective therapy is now available for the prevention and treatment of diabetic complications and it is now possible to extend a high-quality life in diabetic individuals far beyond what was possible 20 years ago.
Multiple Risk Factor Management
Multiple risk factor management is critical in diabetics, especially tight blood pressure control, fastidious cholesterol management, and good glycemic control. Intensive specialist-based management of blood pressure, cholesterol, and glucose was compared with community-based care in a Scandinavian pilot study of type 2 diabetics with microalbuminuria (Steno-2).74 After almost 8 years, the composite end point (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, or amputation) was about 50% less in those receiving intensive care, clearly demonstrating the value of multiple risk factor management.74 Some practitioners currently use microalbumin excretion rates to determine whether an individual requires drug therapy, but there is currently no study that validates the use of microalbuminuria as a clinical indicator for antihypertensive drug therapy.
Prevention vs. Treatment of Target Organ Damage
Based on the results of the SHEP, UKPDS, HOT, ALLHAT, and ABCD studies, it appears safe to say that blood pressure control itself is more important than the choice of drug class in the overall prevention of cardiovascular disease in the metabolic syndrome and diabetes. Once target organ disease is established, however, certain classes of agents may be preferable for the treatment of specific complications of hypertension. Thus, as indicated by the JNC 7 report, a general pattern has emerged that virtually any class of agents (direct evidence exists for thiazide-type diuretics, ACE inhibitors, angiotensin receptor blockers, and calcium antagonists) that maintains tight blood pressure control is an appropriate choice for therapy if target organ damage is not yet present.7 When specific forms of target organ damage exist, there are “compelling indications” for specific antihypertensive drug classes based on existing clinical trials and national guidelines.7 From this overview, certain trends can be discerned. As a general rule of thumb, β blockers and ACE inhibitors are preferred for primary and secondary coronary artery disease prevention in diabetics, whereas ACE inhibitors and angiotensin receptor blockers are preferred in diabetic kidney disease. In the majority of cases, the use of a diuretic is also necessary to achieve goal blood pressure levels <130/80 mm Hg. There is controversy regarding whether calcium antagonists can be beneficial; small studies have revealed that non-dihydropyridine calcium antagonists are more effective in reducing proteinuria than dihydropyridines,75 but the magnitude and long-term significance of this finding is not yet clear.
Goal Blood Pressures
The therapeutic threshold for the definition of hypertension in diabetes is a blood pressure 130/80 mm Hg, a value that appears in the recommendations of the National Kidney Foundation,76 the National High Blood Pressure Education Program's clinical advisory statement on blood pressure care in diabetes,77 and in the JNC 7 report.7 With regard to blood pressure targets in the metabolic syndrome, there are small divergences among the diagnostic thresholds chosen by different guideline committees. ATP-III criteria for the metabolic syndrome include a blood pressure threshold of 130/85 mm Hg, a value that is slightly different from the American Diabetes Association/National Kidney Foundation value76 and JNC 7 guidelines, which use a threshold of 130/80 mm Hg. In reality, because of the overwhelming superiority of systolic blood pressure in risk prediction, the discrepancy between the 80 and 85 mm Hg diastolic values is moot in the vast majority of patients. Generally, if the systolic blood pressure is consistently below 130 mm Hg, the diastolic will be below 80 mm Hg. There is also a current lack of clarity regarding the threshold for drug therapy in the metabolic syndrome. According to JNC 7 guidelines, antihypertensive drug therapy should begin when the blood pressure consistently exceeds 140/90 mm Hg. Thus, individuals with the metabolic syndrome who fall in the range of 130–140 mm Hg/80–90 mm Hg should be counseled to pursue lifestyle modification therapy. If an individual has overt diabetes (fasting blood sugar >125 mg/dL) or chronic kidney disease,* drug therapy is indicated if systolic blood pressure is 130 mm Hg.
Combination Antihypertensive Therapy
Ultimately, any discussion of single-drug therapy is largely moot because combination therapy is essentially unavoidable in the vast majority of patients for physiologic and practical reasons. There are vigorous homeostatic responses to arterial pressure lowering that often overcome the effects of a single antihypertensive agent. Any drug that lowers blood pressure is counteracted by a degree of renal salt and water retention because salt and water excretion are always dependent on glomerular perfusion pressure. There are systemic hemodynamic considerations as well. Systemic blood pressure lowering, especially with a vasodilator or volume-depleting agent, tends to stimulate the defense of blood pressure by the sympathetic nervous system and RAAS. Thiazide-type diuretics are only able to cause volume depletion over the short term; over the long run they reduce vascular resistance and are similar to calcium antagonists and other arterial dilators. Thus, a diuretic or vasodilator is best combined with an anti-RAAS drug (Table II).
|Therapy Level*||Preferred Pathway**||Alternate Pathway**|
|Level 1 (2 drugs)||Diuretic + ACE inhibitor or diuretic + ARB||Calcium antagonist + ACE inhibitor|
|Level 2 (4 drugs)†||Add β blocker + calcium antagonist||Add diuretic +β blocker|
|Level 3 (multidrug)‡||Add/substitute central sympatholytic, α blocker, or arterial dilator|
|ACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker; *lifestyle modification is indicated in all cases; **as suggested in The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,7 initial therapy with two drugs is appropriate if systolic blood pressure is 160/100 mm Hg in uncomplicated hypertension or if systolic blood pressure is 150/90 mm Hg in diabetic individuals or those with chronic kidney disease. Because additional risk reduction is found when systolic blood pressure is reduced below 130/80 mm Hg, combination therapy seems appropriate in almost all individuals with the metabolic syndrome or diabetes, especially to reduce the risk of diabetic renal failure and ischemic heart disease. In general, most combinations should include a diuretic; †concomitant addition of β blocker and calcium dihydropyridine antagonist, either sequentially or together, provides additional theoretical protection against heart failure and stroke. In addition, the use of balanced-drug combinations allows balanced, sustained control of excess extracellular volume, inappropriate neurohormone secretion, and abnormal systemic hemodynamics; ‡advanced therapy requires individual considerations; often a specialist consultation is advisable.|
These theoretical considerations are consistent with practical experience. Roughly speaking, any single antihypertensive drug can be expected to lower blood pressure by about 10/5 mm Hg. The JNC 7 approach has adopted the “20/10 rule,” which states that an individual who is more than 20/10 mm Hg above goal blood pressure will usually require at least two drugs, including 2-drug combinations as initial therapy. Furthermore, it is well described that most individuals with diabetes will require three or more drugs to reach the advanced target value of 130/80 mm Hg.76 Thus, as recommended by JNC 7, most diabetics whose blood pressures exceed 150/90 mm Hg should receive two-drug therapy at the time the diagnosis of hypertension is confirmed.7
Additional drugs are often necessary, and it is often prudent to consider jumping directly from two-drug combinations to four-drug combinations in diabetic individuals to achieve the stringent blood pressure goals that are currently recommended as well as maximizing target organ protective effects (Table II). If the first-level combination is a diuretic plus an anti-RAAS drug, the second level should usually include the addition of both a β blocker and a dihydropyridine calcium antagonist. This four-drug combination is justifiable from a hemodynamic perspective because it is highly attractive to combine a drug that lowers cardiac output (a β blocker) with one that lowers systemic vascular resistance (a dihydropyridine calcium antagonist). From an outcomes perspective, calcium antagonists are highly effective for stroke reduction, while β blockers are effective in treating ischemic heart disease and heart failure. To improve patient acceptance, consideration can be given to fixed-dose combinations. Beyond the four-drug regimen, other agents can be employed or the patient can be referred to a hypertension specialist.
*Chronic kidney disease is present when there is either a reduced estimated glomerular filtration rate (<60 mL/min, equivalent to serum creatinine >1.3 mg/dL in women or >1.5 mg/dL in men) or proteinuria, (24-hour albumin excretion >300 mg/d or spot concentration >200 mg/g creatinine).