Pathophysiologic, Diagnostic, and Therapeutic Aspects of the Metabolic Syndrome

Abstract

The metabolic syndrome, characterized by increases in waist circumference, blood pressure, and triglyceride concentrations combined with reduced high‐density lipoprotein and evidence of glucose intolerance, results from the interaction of visceral or central obesity with insulin resistance. This syndrome presents a clinical situation of systemic inflammation and increased cardiovascular risk. Blood pressure, even if only in the “prehypertensive” range, plays an important role in increasing the risk of cardiovascular disease. Recognition and treatment of each individual component of the metabolic syndrome is critical in reducing cardiovascular risk. Treatment should begin with lifestyle changes, including diet, exercise, and weight reduction. Antihypertensive therapy should be directed toward reduction of blood pressure to levels as close to optimal (<120/80 mm Hg) as feasible, and treatment protocols that do not cause worsening of glucose intolerance should be selected. Therapy for dyslipidemia should be directed at reducing triglycerides and increasing high‐density lipoprotein. Glucose‐lowering agents may be indicated, and drugs such as metformin and thiazolidinediones, which reduce insulin resistance, should form the basis of therapy. Carefully chosen therapy will effectively improve cardiovascular outcomes.

Hypertension may no longer be correctly viewed simply as high blood pressure (BP), but rather must be considered in the context of associated risk factors. More than 80% of individuals with stage 1 or greater hypertension (BP ≥140/90 mm Hg), as defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), ¹ have additional comorbidities, increasing the risk of cardiovascular (CV) complications beyond those that result from the increase in BP alone. These comorbidities include obesity, glucose intolerance, hyperinsulinemia, low high‐density lipoprotein (HDL) levels, elevated low‐density lipoprotein (LDL) and triglyceride levels, left ventricular hypertrophy, and tobacco use²; at least 20% of hypertensive individuals have three or more of these comorbidities. The ultimate impact of BP on CV risk is determined by the number of associated risk factors present (Figure I). ³ , ⁴ , ⁵

Figure 1.

Coronary heart disease risk resulting from interaction of major risk factors. HDL=high‐density lipoprotein. Adapted from Am J Hypertens. 2000;13(suppl 1, pt 2):3S‐10S² and Circulation. 1998;97:1837–1847. ³

Interestingly, these individual risk factors cluster in what has been defined as the CV metabolic syndrome, a proinflammatory condition associated with an increase in CV risk. The metabolic syndrome may actually be considered a CV disease equivalent. ⁶ , ⁷ As an example of this increase in CV risk, participants in the West of Scotland Prevention Study (WOSCOPS) ⁸ identified as having the metabolic syndrome experienced a 76% increase in the risk of a coronary heart disease (CHD) event and a 3.5‐fold increase in the risk of development of new diabetes over 5 years, compared with individuals without these findings.

CHARACTERISTIC FACTORS

Factors characteristic of the metabolic syndrome are: 1) abdominal visceral obesity; 2) atherogenic dyslipidemia (elevated levels of triglycerides and small LDL particles and low HDL cholesterol levels); 3) elevated BP; 4) insulin resistance (with or without glucose intolerance); and 5) prothrombotic and proinflammatory states. The definition of the metabolic syndrome includes certain key criteria, although some variability remains in the less essential elements as applied by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), ⁵ the World Health Organization (WHO), ⁹ and the International Diabetes Foundation ¹⁰ (Table I). ATP III criteria focus primarily on environmental causes of the metabolic syndrome, while the WHO emphasizes the importance of insulin resistance. These differences in diagnostic criteria have clinical implications. Investigators found that 28.1% of a group of 2175 subjects free of CV disease at baseline and not taking antihypertensive or lipid‐lowering medications qualified as having the metabolic syndrome by ATP III criteria, but only 21.0% by WHO criteria; the two sets of criteria provided concordant classification for 80.6% of participants. ¹¹ The metabolic syndrome defined with the ATP III criteria, but not with the WHO criteria, was an independent predictor of coronary or cerebrovascular events during a median follow‐up time of 4.1 years and was associated with a 38% increased risk. We will utilize ATP III criteria for this paper because of its apparent greater sensitivity in identifying patients at risk.

Table I.

Diagnosis of Metabolic Syndrome

Source
	National Cholesterol Education Program (ATP III)5	World Health Organization 9	International Diabetes Federation 10
Criteria*	Three or more of the following:	Glucose intolerance plus two or more of the remaining:	Central obesity plus two or more of the remaining:
Waist circumference (in)		BMI >30 kg/m2 and/or:
Men	>40	waist/hip ratio >0.90	≥43
Women	>35	waist/hip ratio>0.85	≥36
Triglycerides (mg/dL)	≥150	>150	>150
HDL‐C (mg/dL)
Men	<40	<35	<40
Women	<50	<39	<50
Blood pressure (mm Hg)	≥130/85	>140/90	≥130/85
Fasting glucose (mg/dL)	≥110	≥100 <110	≥100
Microalbuminuria	NA	albumin/creatinine ratio ≥30 mg/g	NA
ATP=Adult Treatment Panel; BMI=body mass index; HDL‐C=high‐density lipoprotein cholesterol; NA=not applicable; *active treatment of any criterion is considered the presence of that criterion, regardless of the value with treatment.

BP is generally elevated in the metabolic syndrome, certainly above “optimal.” Since CV risk increases with systolic Bps >115 mm Hg, even pressures in the “high normal” range of <140/80 mm Hg may contribute to risk. ¹² Insulin resistance, observed as hyperinsulinemia with or without glucose intolerance, is a key element, as is a type of atherogenic dyslipidemia commonly seen in diabetes: low HDL and high triglyceride levels. Obesity is abdominal or central, with increased visceral fat, representing the so‐called “apple‐shaped” as differentiated from the “pear‐shaped” configuration; the waist‐to‐hip ratio is specifically addressed in the WHO definition. Waist circumference is a clue to the amount of visceral fat, which while not necessary for the diagnosis, can be quantitated by abdominal CT scanning. Measurement of waist circumference should be made at the level of the umbilicus. A waist circumference of >40 inches for men or >35 inches for women represents an important criterion for the diagnosis of the metabolic syndrome. Additional criteria common to all three definitions include triglyceride concentrations >150 mg/dL and HDL concentrations <40 mg/dL for men and <50 mg/dL for women. There are differences in the requirements for glucose intolerance, with WHO and the International Diabetes Foundation suggesting that glucose concentrations >100 mg/dL indicate potential problems with glucose metabolism. Accurate identification of the extent of glucose intolerance requires measurement of both fasting and 2‐hour postload samples (Table II) ¹³ ; the 2‐hour sample is perhaps a better indicator of the dynamics of insulin secretion and glucose response.

Table II.

Diagnostic Criteria for Glucose Abnormalities

Category	Fasting Glucose (mg/dL)	2 Hour Postload Glucose (mg/dL)*
Normal	<110	<140
Impaired fasting glucose (IFG)	110–125	<140
Impaired glucose tolerance (IGT)	<110	140–199
IGT + IFG	110–126	140–199
Diabetes	≥126	>200
*A 75‐g glucose load is used for evaluating 2‐hour postload glucose values. Adapted from Diabetes Care. 2003;26(suppl 1):S5–S20.13

ATP III and WHO list BP ≥130/85 mm Hg as a criterion for metabolic syndrome; however, there have been suggestions that a more appropriate level would be ≥130/80 mm Hg, or even ≥ 115/75 mm Hg. In diabetic patients, systolic BP is positively associated with the risk for CV death even at systolic pressure levels <120 mm Hg (Figure 2); the risk increases progressively as the level of systolic BP increases. ¹⁴

Figure 2.

The impact of increasing systolic blood pressure on cardiovascular mortality in type 2 diabetes. Adapted from N Engl J Med. 2001;345:1291–1297. ¹²

Insulin resistance appears to drive the CV disease process. ¹⁵ For example, among individuals with type 2 diabetes, the prevalence of the metabolic syndrome is high, and those with diabetes and metabolic syndrome have the highest prevalence of CHD. Among all individuals with diabetes, the prevalence of CHD is increased compared with those with metabolic syndrome without diabetes. The prevalence of CHD in individuals with diabetes without findings of the metabolic syndrome, however, was no greater than in those with neither diabetes nor the metabolic syndrome. ¹⁶ Atherogenic changes in the prediabetic state are mainly seen in insulin‐resistant subjects. ¹⁷ Strategies to prevent type 2 diabetes should therefore focus primarily on insulin‐sensitizing interventions rather than those which may increase insulin resistance and may exert a negative impact on CV risk.

It remains unclear whether the metabolic syndrome represents a constellation of individual but etiologically unrelated abnormalities, or an actual “disease” with a central abnormality expressed as the various components. There may well be a genetic component. A mitochondrial transfer RNA mutation has been identified that leads to a syndrome characterized by hypertension, hyper‐cholesterolemia, and hypomagnesemia. ¹⁸ Insulin deficiency, central obesity, and insulin resistance are closely related (Figure 3); obesity may be the initiating factor, followed by insulin resistance, and ultimately insulin deficiency that may be either relative or absolute. Alternatively, insulin resistance may represent the initial event, followed by obesity, and subsequently an insulin‐deficient state may result from an inability of pancreatic islet cells to maintain an adequate insulin output.

Figure 3.

The interrelationship among central obesity, insulin resistance, and the metabolic syndrome

Central obesity is a unique and critical factor in the metabolic syndrome. All fat cells are not created equal; activities in the small adipocytes in the abdominal visceral fat account for many of the metabolic changes noted in the metabolic syndrome. Visceral adipocytes or fat cells are metabolically active. Visceral adipocytes are insulin resistant, with increased expression of adrenergic receptors, increased catecholamine‐mediated lipolysis, and increased insulin‐mediated antilipolysis, all leading to increased release of plasma free fatty acids. Among the other substances produced by these cells are prostaglandins, angiotensinogen, free fatty acids, the prothrombotic plasminogen activator inhibitor‐1, and inflammatory cytokines such as interleukin‐6 and tumor necrosis factor‐α. Other adipocytes (such as those in subcutaneous fat), in contrast, are composed of small insulin‐sensitive cells with a decreased expression of adrenergic receptors.

The pathophysiologic impact of some of these products is illustrated in Figure 4. Increased angiotensinogen, converted to angiotensin I by renin, leads to production of angiotensin II and aldosterone, and ultimately to vascular constriction. Increased free fatty acids lead to decreased hepatic insulin clearance and hyperinsulinemia, in turn increasing renal sodium reabsorption and ultimately elevations in BP. Inflammation and a prothrombotic state are also enhanced.

Figure 4.

Substances secreted by the visceral fat cell and their relationship to the pathophysiologic features of the metabolic syndrome. ↑=increased; RAAS=renin‐angiotensin‐aldosterone system; PAI‐1=plasminogen activator inhibitor‐1; Il‐6=interleukin‐6; TNF‐α=tumor necrosis factor‐α; CRP=C‐reactive protein; FFA=free fatty acid; LPL=lipoprotein lipase

Inflammation alone contributes significantly to CV risk. C‐reactive protein, produced primarily by the liver when stimulated by interleukin‐6, has a greater predictive value for the development of high BP in middle‐aged normotensive men than does waist girth. ¹⁹ This observation is also true for cigarette smoking ²⁰ ; the inhalation of advanced glycosylation end products used in curing tobacco can induce a chronic inflammatory response.

Many individuals with prehypertension, i.e., systolic BP between 120 and 139 mm Hg and diastolic BP between 81 and 89 mm Hg, have increased concentrations of inflammatory markers. ²¹

MANAGEMENT

The two main goals in the management of patients with the metabolic syndrome are the prevention of progression to overt type 2 diabetes and the prevention of CV disease. ATP III recommendations state that the primary management of the metabolic syndrome should be directed toward reversal of the underlying causes, namely overweight/obesity and physical inactivity. Such therapeutic lifestyle changes, described in more detail in Table III, include caloric restriction, particularly of simple carbohydrates and saturated fats; increase in dietary fiber; increased and regular aerobic exercise; and weight loss. In addition, certain lipid and nonlipid factors (increased BP, the prothrombotic or hypercoagulable state, and dyslipidemia) require specific treatment; such treatment considerations are listed in Table IV and are discussed in detail below.

Table III.

ATP III: Therapeutic Lifestyle Changes

Dietary regimen

• Reduction in saturated fats and cholesterol

• Total fat limited to no more than 30% of intake, with specific reduction in trans fatty acids

• Add three tablespoons of plant stanols/sterols in margarine form

• Add five to nine daily servings of fiber (fruits, vegetables, oat bran, psyllium seed)

Regular physical activity—at least 30 minutes daily of such activities as walking, climbing stairs, housework, or yardwork

Weight loss

Adapted from National Cholesterol Education Program Adult Treatment Panel (ATP) III guidelines. JAMA 2001;285:2486–2497.5

Table IV.

Metabolic Syndrome—Pharmacologic Interventions

Abnormality	Treatment Options
Hypertension	Angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker initial therapy, adding calcium channel blocker* or lowdose thiazide as needed
Dyslipidemia	Statin or fibrate or combination; fibrate preferred for triglycerides >500 mg/dL
Glucose intolerance	Metformin, thiazolidinedione, or combination; avoid insulin if at all possible
Prothrombotic state	Aspirin
*Nondihydropyridine preferred if microalbuminuria or proteinuria present

Lifestyle Modifications

The importance of lifestyle interventions cannot be overestimated. The Diabetes Prevention Program (DPP) ²² demonstrated that in nondiabetic individuals at high risk for development of diabetes, lifestyle modifications reduced the incidence of new diabetes by 58% vs. 31% by metformin. The Finnish Diabetes Prevention Study ²³ was able to demonstrate a 58% reduction in the risk of diabetes in a group of overweight subjects with impaired glucose tolerance who underwent extensive lifestyle intervention including individualized counseling aimed at reducing weight and total intake of fat (particularly saturated fat) and increasing intake of fiber, plus increasing physical activity. In a comparative study over a 3‐year period, the Chinese Prevention Trial ²⁴ demonstrated a 43% reduction in the development of diabetes by a diet and exercise program, but there was an 88 % reduction with acarbose and a 77% reduction with metformin. A 5‐lb weight loss in obese subjects has been estimated to produce a 10% reduction in BP. ²⁵

Dyslipidemia

Specific pharmacologic therapy includes statins and fibrates. A recently published meta‐analysis of data from 25 studies evaluating the effect of statin therapy in CHD patients demonstrated a 16% reduction in all‐cause mortality, a 23% reduction in CHD mortality, and a 25% reduction in CHD mortality or nonfatal myocardial infarction. ²⁶ The Heart Protection Study (HPS) ²⁷ demonstrated that major acute coronary events are reduced as much in diabetic subjects as in nondiabetics. These studies, however, focused primarily on reducing LDL cholesterol levels. The particular dyslipidemia of the metabolic syndrome is not, however, generally characterized by high LDL levels, but rather by average‐to‐low LDL levels with low levels of HDL and high levels of triglycerides and atherogenic small dense lipoprotein particles, including very low‐density lipoprotein remnants rich in apolipoprotein C‐III content. The fibrates, as peroxisome proliferator‐activated receptor (PPAR)‐α activators, may be particularly suited pharmacologically to treat this profile of dyslipidemia. Gemfibrozil was tested in the Veterans Affairs Cooperative Studies Program High‐Density Lipoprotein Cholesterol Intervention Trial (VA‐HIT) ²⁸ in patients with coronary events but relatively low LDL levels. At 1 year, the mean HDL level was 6% higher, the mean triglyceride level was 31% lower, and the mean total cholesterol level was 4% lower in the gemfibrozil group than in the placebo group; LDL levels did not differ significantly between the groups. After a median of 5.1 years, the investigators observed a 24% reduction in the combined outcome of death from CHD, nonfatal myocardial infarction, and stroke. Fenofibrate has been demonstrated to be more effective than atorvastatin in increasing HDL levels in nondiabetic subjects with low HDL levels (13.3% vs. 5.3%, respectively). ²⁹

The Diabetes Atherosclerosis Intervention Study (DAIS) evaluated the ability of micronized fenofibrate to reduce the angiographic progression of coronary artery disease in type 2 diabetic subjects with dyslipidemia but with reasonably good glycemic control (mean glycosylated hemoglobin level, 7.5%). ³⁰ The fenofibrate group showed a significantly smaller increase in diameter stenosis, a smaller decrease in minimal luminal diameter, and a nonsignificant, smaller decrease in mean segment diameter. Although the trial was not powered to detect clinical end points, there were fewer in the fenofibrate group than in the placebo group. Fenofibrate significantly reduced levels of total cholesterol, LDL, and triglycerides, and increased HDL levels, relative to placebo. Combination therapy with a statin and a fibrate may yield even greater benefits. When patients with mixed hyperlipidemias were randomized to receive either atorvastatin, fenofibrate, or the combination, lipoproteins were changed to a greater extent with combined therapy than with either drug alone.

Flow‐mediated dilator responses to hyperemia and plasma high‐sensitivity C‐reactive protein and fibrinogen levels were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone. The effects of combined therapy or fenofibrate alone on plasma adiponectin levels and insulin sensitivity were greater than those of atorvastatin alone. ³¹

Hypertension

Effective reduction of BP is perhaps the most important element in reducing CV risk. Results from the United Kingdom Diabetes Prevention Study (UKDPS) ³² indicated that each 10 mm Hg decrease in mean systolic BP reduced all CV event rates, both microvascular and macrovascular, by 12%; there was also a 12% reduction for any complication related to diabetes, 15% for deaths related to diabetes, 11% for myocardial infarction, and 13% for microvascular complications. As further demonstrated in UKPDS data, “tight” BP reduction (an achieved BP of 144/82 mm Hg compared with 154/87 mm Hg, a difference of 10/5 mm Hg) is more effective than “less tight” glucose reduction in achieving event reduction. ³³ Results of treatment of the diabetic cohort in the Systolic Hypertension in the Elderly Program (SHEP) ³⁴ demonstrate the significant benefit of BP reduction, despite the fact that the target pressures were considerably above what we now consider appropriate. The 5‐year major CV disease event rate was lower by 34% for active treatment compared with placebo, both for diabetic patients and nondiabetic patients; the absolute risk reduction, however, with active treatment compared with placebo, was twice as great for diabetic compared with nondiabetic patients (101/1000 vs. 51/1000 randomized participants at the 5‐year follow‐up), reflecting the higher risk present with diabetes. The Systolic Hypertension in Europe (SYS‐Eur) trial, ³⁵ utilizing a treatment regimen based on the calcium channel blocker (CCB) nitrendipine, demonstrated a 76% reduction in CV mortality in diabetic patients as compared with a 13% reduction in nondiabetics.

In patients with diabetes, antihypertensive therapy should include agents that inhibit the renin‐angiotensin system ¹ , ³⁶ ; this recommendation is based on the established activation of the renin‐angiotensin system in diabetes and supported by data from numerous clinical trials. Such agents include the angiotensin‐converting enzyme (ACE) inhibitors and the angiotensin receptor antagonists (ARBs). The Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) ³⁷ demonstrated that, although an amlodipine‐based regimen was more effective than a fosinopril‐based regimen in reducing systolic BP (−19 mm Hg vs. −13 mm Hg, respectively), the fosinopril group showed a significant reduction in the combined end point of myocardial infarction, stroke, and hospitalization for angina. The Appropriate Blood Pressure Control in Diabetes Trial (ABCD), ³⁸ comparing treatments with nisoldipine‐ and enalapril‐based regimens, demonstrated similar findings. ACE inhibitors and ARBs appear to be equivalent in reduction of CV and renal risk, as demonstrated in a comparison of the ACE enalapril with the ABR telmisartan in a 5‐year trial in diabetic patients. ³⁹ In another study, both an ACE inhibitor, an ARB, or their combination significantly reduced C‐reactive protein and oxidized LDL cholesterol serum levels in type 2 diabetes patients who were free of coronary artery disease, demonstrating a positive effect on inflammation and lipid peroxidation. ⁴⁰

A number of trials have demonstrated that treatment with an ACE inhibitor‐ or ARB‐based regimen reduces the incidence of new diabetes relative to treatment with thiazides and β blockers, particularly when these latter drugs are combined. The differing effects of these drugs on progression to diabetes are revealed by analysis of the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ⁴¹ data. Chlorthalidone, although more effective than lisinopril in reducing BP, was associated with a higher incidence of new diabetes after 4 years. CV outcome, was not, however, affected by this occurrence. A review of data from 58,010 patients treated in hypertension trials demonstrated that ACE inhibitors and ARBs reduced new diabetes by 20%, and CCBs by 16%, relative to thiazides and β blockers. ⁴² The absolute risk increase is 1%–3.5% between an ACE inhibitor and diuretic and about 1%–1.5% between a CCB and diuretic plus β blocker treatment. ⁴³ It has been demonstrated in one study that diabetes occurring during treatment has the same adverse prognostic implications as does new‐onset diabetes in the absence of antihypertensive treatment, especially in higher‐risk patients, ⁴⁴ although a follow‐up of the SHEP study did not confirm this. ⁴⁵ The converse of this observation might be that treatment with thiazides is associated with an increased rate of new diabetes, beginning in individuals with a fasting glucose as low as 90–95 mg/dL; in other words, in the normal range. Placebo‐controlled diuretic studies demonstrated a <10% increase in hyperglycemia or new‐onset diabetes. ⁴⁶ Data from the International Verapamil‐Trandolapril Study (INVEST) ⁴⁷ suggested that hydrochlorothiazide doses as small as 12.5 mg/d could offset the protective effect of ACE inhibition against the onset of new diabetes. It may be prudent therefore, despite the fact that the occurrence of new‐onset diabetes has not affected outcome in the clinical trials, to utilize thiazides and especially β blockers with caution in patients with the metabolic syndrome, and then only when necessary to achieve optimal BP reduction and only in combination with ACE inhibitors or ARBs to offset the hyperglycemic effect.

Avoidance of Progression to Diabetes

Studies discussed earlier that compared lifestyle modifications with treatment with active hypoglycemic agents such as metformin and acarbose demonstrated benefit for these pharmacologic agents. Another class of agents, the thiazolidinediones (pioglitazone and rosiglitazone), may deserve special consideration. These agents are PPAR‐γ agonists that exert not only hypoglycemic effects via insulin‐sensitizing effects, but exert significant effects on lipid metabolism and inflammation. ⁴⁸ The PPARs are a family of nuclear receptors that exert profound effects on vascular function and lipid metabolism. The fibrates, as PPAR‐α agonists, increase apolipoprotein A‐I, apolipoprotein A‐II, lipoprotein lipase, and the activity of the scavenger receptor class B type 1 receptors and adenosine triphosphate‐binding cassette Al receptors; their efficacy has been considered earlier in this paper. The DPP was a randomized clinical trial to determine prevention of type 2 diabetes in high‐risk individuals; treatment arms included troglitazone, a PPAR‐γ agonist and insulin‐sensitizing agent no longer available for clinical use; metformin; lifestyle modifications; and placebo. ⁴⁹ Troglitazone was withdrawn after a mean treatment period of 0.9 year. At that interval, however, the diabetes incidence rate with troglitazone was 3.0 cases/100 person‐years, compared with 12.0, G.I, and 5.1 cases/100 person‐years in the placebo, metformin, and intensive lifestyle‐moderation groups, respectively. This effect of troglitazone was in part due to improved insulin sensitivity with maintenance of insulin secretion. During the 3 years after troglitazone withdrawal, the diabetes incidence rate was almost identical to that of the placebo group. Due to the essential contribution of insulin resistance to the development of the metabolic syndrome, treatment with insulin should be avoided.

SUMMARY

Although the metabolic syndrome may be defined in several ways, certain key features include central obesity and insulin resistance leading to glucose intolerance and atherogenic dyslipidemia. The presence of metabolic syndrome predicts the development of both overt type 2 diabetes and CV disease with such accuracy that it should be considered a CV disease equivalent. Treatment should be directed at all aspects of the syndrome, beginning with lifestyle modifications, particularly for adolescents and young adults, and continuing with pharmacologic interventions as indicated to reduce BP, dyslipidemia, and glucose abnormalities. Although not specifically addressed in this paper, aspirin should be included as an antithrombotic agent; doses between 75 mg/d and 325 mg/d appear equally efficacious. ⁵⁰ A clinical trial has now clearly demonstrated that aggressive treatment of individual abnormalities markedly improves clinical outcomes. Steno‐2, ⁵¹ a trial in type 2 diabetic subjects, randomly assigned 80 patients to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of CV disease with aspirin. Treatment goals included glycosylated hemoglobin concentrations <6.5%, BP <130/80 mm Hg, total cholesterol levels <175 mg/dL, and triglyceride levels <150 mg/dL. Patients receiving intensive therapy had a significantly lower risk of CV disease (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.24–0.73), nephropathy (HR, 0.39; 95% CI, 0.17–0.87), retinopathy (HR, 0.42; 95% CI, 0.21–0.86), and autonomic neuropathy (HR, 0.37; 95% CI, 0.18–0.79).

The critical importance of recognizing and treating the metabolic syndrome is now clear. Guidelines are available to appropriately characterize individuals with this syndrome, as well as to suggest appropriate treatment protocols. BP control should probably begin with, or certainly include, antihypertensive agents such as ACE inhibitors and ARBs that block the renin‐angiotensin‐aldosterone system. Dyslipidemias are addressed primarily with statins and fibrates, with fibrates perhaps preferred in the presence of very high triglyceride levels (>500 mg/dL) and low HDL levels; combinations of these drugs may have additional benefits over monotherapy. Early treatment for glucose intolerance might well include the insulin‐sensitizing agent metformin and, in some instances, thiazolidinediones; metformin presents an initial advantage of associated weight loss. Insulin should be avoided if at all possible. The message is to treat aggressively and to treat to targets; this will result in maximal patient benefit.