OVERVIEW

The risk for coronary heart disease (CHD) is 3-4 times higher for patients with type 2 diabetes mellitus than for lean people without diabetes. Having diabetes is currently considered a risk equivalent to having had a myocardial infarction. Numerous studies have shown that endothelial dysfunction, an early stage of the atherosclerotic process, occurs in patients with type 2 diabetes. Similar vascular abnormality has also been observed in nondiabetic individuals who are obese and in individuals who are at high risk for developing diabetes, including those with impaired glucose tolerance and normoglycemic first-degree relatives of patients with type 2 diabetes.

Although the exact pathogenesis of endothelial dysfunction in these populations is not yet fully understood, multiple mechanisms are probably involved. Some evidence indicates that diabetes-related endothelial cell injury results in decreased nitric oxide production. Other evidence suggests that degradation of nitric oxide by oxygen-derived free radicals and advanced glycation end products may be accelerated in the hyperglycemic state.

Tumor necrosis factor-alpha (TNF-a), the level of which is significantly increased in diabetic individuals, is a main inducer of inflammation and is considered a major independent risk factor for atherosclerosis and CHD. In humans, TNF-a serum levels inversely correlate with insulin sensitivity. The mechanism by which TNF-a induces insulin resistance is still not fully understood. Evidence suggests that TNF-a is associated with the down-regulation of GLUT4 mRNA in adipose tissue and skeletal muscles and with a reduction in insulin receptor substrate-1.

TNF-a acts as a higher-order cytokine that influences the synthesis, secretion, and activity of other cytokines that affect the endothelium, such as IL-6, plasminogen activator inhibitor-1 (PAI-1), and leptin. At a molecular level, TNF-a increases monocyte adhesion to vascular endothelium, activates nuclear factor kB (NF-kB)–dependent proinflammatory pathways, and induces endothelial cell expression of the vascular adhesion molecule (VCAM-1) and endothelin-1. It also induces smooth muscle expression of matrix metalloproteinases, thus contributing to plaque destabilization. Conversely, reversal of the TNF-a effect or reduction in its signaling through the downstream IKKb/NF-k pathway improves insulin sensitivity and endothelial function.

LINK BETWEEN DIABETES AND CARDIOVASCULAR DISEASE

An elevation in the level of the circulating forms of the adhesion molecules in diabetes has been reported, along with associated development of atherosclerosis. People with diabetes also have higher plasma levels of PAI-1 than those without diabetes. Through several mechanisms, elevated PAI-1 levels increase thrombotic tendency. PAI-1 is known to inhibit the action of plasminogen activator and the dissolution of fibrin deposits on the luminal side of the vessel wall. In addition, it also decreases vascular smooth muscle cell migration and expression of urokinase within the vessel wall and in the atherosclerotic plaque. In addition to the effects of PAI-1, increased circulating cytokines and growth factors and their consequent subclinical inflammation is currently viewed as a possible key factor in the etiology of atherosclerosis and diabetes.

Low adiponectin serum concentration was also observed with obesity, type 2 diabetes, and coronary artery disease, in both mice and humans. Adiponectin is involved in the modulation of inflammatory responses both by its anti-inflammatory effect and by its specific function in the blood vessel wall. Adiponectin attenuates tumor TNF-a-mediated inflammatory response. It also inhibits some functions of mature macrophages, such as phagocytosis and cytokine production, which are essential for continuation of the atherosclerotic process.

ROLE OF DIABETES TREATMENT IN REDUCING CARDIOVASCULAR RISK

Several medications have been shown to reduce cardiovascular risk in patients with diabetes.

• The United Kingdom Prospective Diabetes Study (UKPDS) reported that use of metformin was associated with a reduction in cardiovascular events compared with use of sulfonylureas or insulin.
  
• Recent studies have shown that thiazolidinediones (TZDs) have a favorable effect on circulating cytokines and that their antiatherogenic effect, as evident by their effect on CRP and pulse wave velocity, is independent of their hypoglycemic effect.
  
• TZDs, particularly pioglitazone, favorably affect the lipid profile by lowering the serum triglyceride level, increasing LDL-cholesterol particle size, and reducing LDL-cholesterol particle density. Treatment with TZDs has also been shown to increase the adiponectin level.
  
• Rosiglitazone therapy for 6 months has been accompanied by a more than twofold increase in the adiponectin level. The TZD-induced increase in adiponectin was not affected by coadministration of glyburide or metformin.

Obese patients with type 2 diabetes who lost weight, either through diet restriction and increased physical activity or through medications, experienced improved insulin sensitivity and endothelial function, reduced key markers of endothelial activation, diminished inflammation and coagulation, and increased adiponectin serum levels. Whether sustained weight reduction in patients with type 2 diabetes results in significant decline in the risk of cardiovascular events is not yet known. The ongoing Look AHEAD (Action for Health in Diabetes) study, which is expected to be complete in 2011, may answer this important question.

PREVENTION OF CHD IN DIABETES AND FUTURE TARGETS OF THERAPY

In the recent placebo-controlled Collaborative Atorvastatin Diabetes Study (CARDS), 10 mg of atorvastatin daily for 4 years effectively reduced the risk of a first major cardiovascular event, including stroke, in patients with type 2 diabetes and at least 1 other CHD risk factor, without markedly elevated LDL-C levels. Thus, atorvastatin has a potential role in the primary prevention of cardiovascular events in diabetic patients at risk for CHD, regardless of pretreatment LDL-C levels. Currently, the consensus is that LDL-C levels in diabetic individuals should be reduced to less than 70 mg/dL in order to achieve maximal cardioprotection.

Results from controlled prospective clinical trials justify the use of enteric-coated low-dose aspirin (81-325 mg) as a primary or secondary prevention strategy in diabetic adults older than 30 years who are at high risk for cardiovascular events. Recent studies support the use of clopidogrel in addition to standard therapy, as well as the use of platelet glycoprotein (Gp) IIb/IIIa inhibitors in patients with acute coronary syndrome (ACS). In a meta-analysis of 6 trials studying diabetic patients with ACS, intravenous GpIIb-IIIa inhibitors reduced the 30-day mortality rate compared with that of control subjects.

The Heart Outcomes Prevention Evaluation (HOPE) Study and the Microalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation (MICRO-HOPE) substudy demonstrated that 10 mg of ramipril significantly lowered the risk of myocardial infarction, stroke, cardiovascular death, and total mortality in diabetic people aged 55 years or older who had a previous cardiovascular event or at least 1 other cardiovascular risk factor and who did not have clinical proteinuria, heart failure, or low ejection fraction. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. On the other hand, reduction of diastolic blood pressure to less than 80 mm Hg is currently considered the optimal target for the diabetic population.

Inhibiting inflammation through interference with the IKKb/NF-k inflammatory pathway is a worthwhile goal for future medications. Recombinant adiponectin and/or TZDs with stronger hypolipidemic effects are other potential treatments of CHD and type 2 diabetes.

References

Abbasi F, Chu JW, McLaughlin T, et al. Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus. Metabolism 2004; 53(2): 159-64.

Caballero AE, Arora S, Saouaf R, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 1999; 48(9): 1856-62.

Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364(9435): 685-96.

Gray RP, Yudkin JS, Patterson DL. Plasminogen activator inhibitor: a risk factor for myocardial infarction in diabetic patients. Br Heart J 1993; 69(3): 228-32.

Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339(4): 229-34.

Hamdy O, Ledbury S, Mullooly C, et al. Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care 2003; 26(7): 2119-25.

Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355(9200): 253-9.

Matsuda M, Shimomura I, Sata M, et al. Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 2002; 277(40): 37487-91.

Satoh N, Ogawa Y, Usui T, et al. Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 2003; 26(9): 2493-9.