Type 2 Diabetes, the Metabolic Syndrome, Inflammation, and Arteriosclerosis:

Up to 10% of Americans older than 20 years have type 2 diabetes, and more than 20% have the metabolic syndrome.^1,2 The prevalence of both diseases has risen by 33% over the past decade as a result of an increasingly sedentary lifestyle, the obesity epidemic, the growth of ethnic groups at risk for the disease, and the aging of the population. The prevalence of the metabolic syndrome increases dramatically with age: 45% of persons older than 60 years are thought to have the syndrome. Type 2 diabetes mellitus will develop in many of these persons.^1,2

In the United States, diabetes is the fifth leading cause of death; the leading cause of kidney failure, nontraumatic limb amputations, and blindness; and the foremost contributor to cardiovascular disease (CVD). CVD accounts for about 70% of deaths in adults with diabetes and is a stronger predictor than glycemic control of morbidity and use of health care resources in these patients.^3-6 Moreover, 3 components of the metabolic syndrome--hypertension, glucose intolerance, and dyslipidemia--are major risk factors for CVD.

Despite better understanding of the pathophysiology and management of diabetes and the metabolic syndrome, patient outcomes have not shown a parallel improvement.^7,8 Only 30% to 35% of patients with diabetes achieve 1 or more of the American Diabetes Association goals for the quality indicators of hemoglobin A_1c, low-density lipoprotein cholesterol (LDL-C), and blood pressure (BP). Only 7% of patients achieve goal levels in all 3 indicators.⁹

Our current system of medical education and clinical care has not effectively addressed this issue. A major shift in the way we care for patients is crucial to reduce the burden of suffering associated with diabetes and the metabolic syndrome and to forestall the development of CVD.

A CASE IN POINT

The following case, a typical one seen in primary care, serves as a good framework to aid our understanding of the problem and how it might be addressed.

A 42-year-old Hispanic man presented for a physical examination at his wife's urging, although he had no specific complaints. He had recently gained 10 lb, which he attributed to the elimination of his daily walking and a new job that involved more deskwork. He had a family history of diabetes, and his father had had a stroke at age 60 years.

The patient's body mass index (BMI) was 29, his waist circumference was 42 inches, and his BP was 138/88 mm Hg. Other examination results were normal. His fasting laboratory results included a serum glucose level of 108 mg/dL; total cholesterol, 190 mg/dL; LDL-C, 100 mg/dL; high-density lipoprotein cholesterol (HDL-C), 30 mg/dL; and triglycerides, 300 mg/dL.

Consider the following questions as you continue reading: With the above history, examination, and laboratory values, what is the patient's risk of a cardiovascular event? How would you treat this man? Would you prescribe anything other than diet and exercise?

The patient was advised to exercise and to reduce his intake of saturated fat. During the next 8 years, he returned on several occasions for acute conditions such as upper respiratory tract infections and knee pain. His BP had risen to 148/94 mm Hg, and hydrochlorothiazide, 25 mg/d, was started. No further laboratory tests were performed during that period.

At age 50 years, he was admitted to the hospital with a myocardial infarction (MI). His serum glucose level was 350 mg/dL; the hemoglobin A_1c was 9. His lipid levels were unchanged. He was treated with metformin, and his hemoglobin A_1c decreased to 7.5. Because his LDL-C level was 100 mg/dL, no treatment was prescribed for his other lipid abnormalities. A b-blocker was added for hypertension; his BP averaged about 140/85 mm Hg. Three years later, he had a stroke.Five years after that, at age 58 years, he had a massive MI and died.

REEVALUATING RISK

Given our current knowledge, could his MI, stroke, and premature death have been prevented? In trying to make that assessment, let us go back and calculate his risk at age 42 years. According to the risk calculator recommended by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]), the patient's risk of a cardiovascular event in the next 10 years was 2% to 3%.¹⁰

These calculations are driven by many factors, the most important of which is age. Projecting age forward with the calculator and not changing the risk factors, an increase in risk is apparent. By age 55 years, the risk increases to 16%, and by age 60 years, it increases to 20%. However, if the patient's diabetes had been included in the calculation by age 50 years, the risk would have been 20% at that age. Risk calculators can give a false sense of security in younger persons; projecting forward gives a more realistic assessment.

The other critical factor in this patient is his lipid profile. At first glance, his LDL-C level seems ideal. However, this is misleading because it is a calculated value. The calculation is not valid when the triglyceride level is higher than 200 mg/dL; this patient's level was 300 mg/dL. ATP III recommends using non-HDL-C instead of LDL-C to help make management decisions when triglyceride levels are higher than 200 mg/dL.¹⁰ The non-HDL-C level is total cholesterol minus HDL-C, which in this patient is 160 mg/dL (190 2 30 = 160).The ideal non-HDL-C level is 100 to 130 mg/dL in patients who are at elevated risk for CVD.

This patient also had atherogenic dyslipidemia (high triglyceride and low HDL-C levels). This combination indicates a high concentration of small, dense LDL-C particles that are highly atherogenic and can lead to significant CVD if not treated.

More aggressive treatment would certainly have been warranted in this patient. At a minimum, in addition to significant changes in his diet and level of physical activity, much closer follow-up of his lipid status and hemoglobin A_1c was warranted. If his non-HDL-C level had failed to decrease to 130 mg/dL or less with lifestyle changes, statin therapy should have been strongly considered.

A test for high-sensitivity C-reactive protein (hsCRP) is more sensitive than the test for CRP and would also have helped guide this patient's treatment. An elevated value (ie, higher than 3 mg/L) would have placed him in a high-risk category that required aggressive treatment. His elevated BP warranted use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), in addition to the diuretic, to reduce his BP to more acceptable levels. Because he had diabetes, an acceptable goal according to current recommendations would be less than 130/80 mm Hg.¹¹

METABOLIC ABNORMALITIES IN THE METABOLIC SYNDROME AND TYPE 2 DIABETES

This patient had the metabolic syndrome. The Table lists 5 diagnostic criteria; only 3 are required to make the diagnosis. This patient had all 5 criteria.

Most patients with the metabolic syndrome have insulin resistance,^1,2 and diabetes will develop in many of these persons. In patients with insulin resistance, biologic impairment leads to decreased glucose uptake in skeletal muscle, increased release of free fatty acids (FFAs) into the serum from adipocytes, and a paradoxical increased production of hepatic glucose because of hyperglycemia. Pancreatic insulin secretion is also blunted by the increase in FFAs.¹²Figure 1 depicts the biologic impairment and resulting metabolic defects in diabetes. Many of these defects are also present in the metabolic syndrome. Note how the increase in FFAs affects all the other metabolic defects.

Initially, patients with insulin resistance produce large amounts of insulin that prevent hyperglycemia. In many of these patients, pancreatic function eventually will deteriorate and hyperglycemia and diabetes will develop. However, the other abnormalities&mdashsuch as atherogenic dyslipidemia and hypertension-are in place long before hyperglycemia appears and increases the risk of CVD. Unfortunately, it is not unusual for a diagnosis of diabetes not to be made until after patients have a stroke or MI, as in the case discussed here. If the risk of CVD is recognized and treatment initiated earlier, the incidence of cardiovascular events will decrease.

ROLE OF INFLAMMATION IN CVD

At one time, we believed that gradual narrowing of the arteries over time led to cardiovascular events such as stroke and MI. We now understand that arterial obstruction occurs acutely, secondary to rupture of an arterial plaque and formation of a clot that obstructs the artery.¹³ Atherosclerosis is a dynamic inflammatory disease in which metabolic risk factors such as LDL-C interact with immune mechanisms to threaten the structural integrity of plaque and precipitate cardiovascular events.¹⁴ The small, dense LDL-C particles, which are more numerous in the metabolic syndrome and diabetes, stimulate inflammatory cells to secrete degrading enzymes that deplete collagen in the intima of the arterial wall. This leads to plaque instability and susceptibility to rupture.¹⁴

The key to plaque stability is the fibrous cap: the thicker the cap, the more stable the plaque. The integrity of the fibrous cap depends on the balance of synthesis and breakdown of the matrix materials in the cap. Inflammatory forces shift this balance toward the breakdown of matrix materials and plaque rupture. Thin fibrous caps contain an increased number of inflammatory cells and are more susceptible to rupture.¹⁴

Adipocytes (fat cells) are the site of the inflammatory process.The adipocytes become dysfunctional because of insulin resistance and release FFAs into the plasma. The increase in circulating FFAs contributes to a rise in hepatic triglyceride levels, which in turn enhances the production of small, dense LDL-C particles.¹⁵ The dysfunctional adipocytes also release inflammatory cytokines, such as tumor necrosis factor and interleukin-6.¹⁶

Markers of inflammation. hsCRP is a surrogate marker for inflammation and cardiovascular risk. Levels of hsCRP higher than 3 mg/L are stronger predictors of future events than are LDL-C and non-HDL-C levels.¹⁷ Values higher than 10 mg/L indicate a noncardiovascular cause; in this case, the test should be repeated in a few weeks. Elevated levels of hsCRP predict type 2 diabetes and can help stratify risk levels in patients with the metabolic syndrome and a family history of heart disease. It is helpful to measure hsCRP in patients who seem to be at low or intermediate risk, such as the man in the case discussed here. If the hsCRP level is high, more aggressive treatment is indicated. Two recent studies suggest that hsCRP may be used to monitor patients and gauge the effectiveness of therapy. The REVERSAL study demonstrated that hsCRP predicted progression of atherosclerosis independent of LDL-C levels.¹⁸ The PROVE-IT study demonstrated an increased incidence of cardiovascular events with higher hsCRP levels and a decreased incidence with lower hsCRP levels.¹⁹More long-term studies are needed to support an evidence-based recommendation.

POSSIBLE TREATMENT OPTIONS

The only evidence-based treatment for the metabolic syndrome is lifestyle changes. No drugs are currently indicated for this syndrome; however, drugs are approved for specific components of the syndrome. The ATP III guidelines recommend reductions of LDL-C to below 70 mg/dL in patients who have the metabolic syndrome and coronary heart disease.²⁰

According to a recent statement from the American Diabetes Association, until randomized controlled trials have been completed, no appropriate pharmacologic treatment for the metabolic syndrome can be recommended.²¹ In contrast, the American Heart Association/National Heart, Lung, and Blood Institute recently recommended drug therapy if lifestyle changes fail to modify risk factors.²² I think that clinicians should use their own judgment and balance the potential benefits against the risks of pharmacologic therapy. In patients with multiple risk factors, the evidence overwhelmingly indicates that risk reduction will reduce morbidity and mortality. Certain treatment options--such as therapeutic lifestyle changes, aspirin, statins, ACE inhibitors, and ARBs--are less controversial than the use of metformin and the glitazones. The following discussion should help in the decision-making process.

Lifestyle changes. These changes form the basis for treatment of the metabolic syndrome. Weight loss and exercise in patients with truncal/visceral obesity are associated with substantial reductions in major atherogenic risk factors. A 10% loss of body weight corresponds roughly to a 30% loss of adipose tissue. A decrease in the amount of adipose tissue leads to a decrease in levels of hsCRP and other inflammatory cytokines, which results in improved endothelial function, decreased BP,lower levels of LDL-C, and increased levels of HDL-C.²³ When advising patients, remember how difficult it is for them to start and sustain any changes. Patients usually think that they do not have the ability to succeed. Change is more likely to occur if a clinician first gains a patient's trust and confidence, then gives advice.

Aspirin. Aspirin therapy is recommended for patients who are at moderate to high risk for cardiovascular events, including those with the metabolic syndrome. Adipose tissue in patients with the metabolic syndrome or diabetes produces increased amounts of plasminogen activator inhibitor (PAI)-1.¹⁶ Elevated levels of PAI-1 increase the risk of clotting when a plaque ruptures; aspirin reduces the risk. Aspirin also lowers the elevated levels of hsCRP typically found in high-risk patients; this reduction is associated with a significantly decreased risk of MI and stroke.²⁴

Statins.Hyperglycemia is a weak predictor of CVD compared with hypertension and hyperlipidemia. Statins are an important option in treating the inflammatory cascade created by diabetes and the metabolic syndrome. These agents decrease LDL-C levels and reduce the risk of CVD and stroke.^25,26 Many patients with diabetes or the metabolic syndrome have normal levels of LDL-C; however, regardless of the initial values, lower is better in patients who are at risk for a cardiovascular event.

Studies have demonstrated that production of nitric oxide begins to drop when LDL-C levels are above 60 mg/dL.²⁷ Nitric oxide is a powerful vasodilator and decreases inflammation at the endothelial level. Oxidized LDL-C (one of the main culprits in endothelial dysfunction) is created at the expense of nitric oxide creation. The Heart Protection Study and the ASCOT-LLA study support the recommendation of lower LDL-C levels in at-risk patients.^26,28 These studies also reinforce the idea that effective reduction of cardiovascular risk depends on global risk assessment. The metabolic syndrome offers a means of assessing global risk.

Two recent studies demonstrated that statin therapy decreased hsCRP and LDL-C levels, and that this reduction stabilized plaque and reduced the risk of rupture.^18,19

ACE inhibitors and ARBs. These agents, which effectively treat hypertension, are first-line therapy in persons with diabetes. Both classes of drugs reduce insulin resistance and thus may benefit patients who are at high risk for diabetes, such as those with the metabolic syndrome. A recent meta-analysis of 11 trials (6 used ACE inhibitors and 5 used ARBs) demonstrated a decreased risk of diabetes.²⁹ Reduction of insulin resistance and a decreased risk of diabetes are compelling reasons to consider ACE inhibitors and ARBs in patients with the metabolic syndrome.

Oral antidiabetic agents. Figure 2 shows the specific sites of action of oral antidiabetic agents. Because diabetes develops in many patients with the metabolic syndrome and both conditions are strongly related to insulin resistance, it seems reasonable to consider using the same therapeutic agents that are effective in diabetes for the metabolic syndrome. The biguanides and the thiazolidinediones not only reduce serum glucose levels but also mitigate some of the risk factors for CVD, which makes them attractive options for the metabolic syndrome.

Metformin acts principally on the hepatic production of glucose by inhibiting gluconeogenesis. It has a small effect on muscle uptake of glucose.³⁰ In the UK Prospective Diabetes Study (UKPDS), patients treated with metformin had a 30% reduction in cardiovascular events and mortality compared with those who received conventional treatment.³¹ Metformin also reduces levels of triglycerides and LDL-C.³²

The thiazolidinediones act primarily on adipocytes by decreasing lipolysis and the production of FFAs. The decrease in FFAs enhances the muscle uptake of glucose and promotes beta-cell function in the pancreas. These agents may also preserve beta-cell function by decreasing apoptosis of beta cells.³³

Thiazolidinediones increase HDL-C and LDL-C levels; pioglitazone decreases triglyceride levels.³⁴ The thiazolidinediones also increase endothelium-derived nitric oxide production. Nitric oxide raises HDL-C levels and lowers triglyceride levels. Decreased nitric oxide production in diabetes contributes to hypertension and endothelial dysfunction.³⁵

Thus, although the thiazolidinediones and metformin are used to treat the hyperglycemia of diabetes, they may--because of their multiple effects on lipids, hypertension, and endothelial function--have a role in the treatment of the metabolic syndrome.³³ Polycystic ovary syndrome is a good example of a disorder in which both of these drugs positively affect an insulin-resistant state.^36,37