Diabetes and Cardiovascular Risk Markers

Key words: Cardiovascular disease – Dyslipidaemia – Insulin resistance – Metabolic syndrome – Thiazolidinedione – Type 2 diabetes

ABSTRACT

Background: People with type 2 diabetes generally carry an array of risk factors for cardiovascular disease (CVD), including hyperglycaemia, dyslipidaemia, alterations in inflammatory mediators and coagulation/ thrombolytic parameters, as well as other ‘non- traditional’ risk factors, many of which may be closely associated with insulin resistance. Consequently, rates of CVD mortality and morbidity are particularly high in this population. Targeting hyperglycaemia alone does not reduce the excess risk in diabetes, highlighting the need for aggressive treatment of other risk factors.

Scope: This is a review of cardiovascular risk markers in diabetes, based on MEDLINE and EMBASE literature searches (1994- 2004).

Findings: Although, the current use of statin therapy is effective at reducing low-density lipoprotein (LDL)-cholesterol, residual risk remains from other independent lipid and non-lipid factors. The peroxisome proliferator-activated receptor-γ (PPARγ) appears to be intimately involved in regulating risk markers at multiple levels. Ligands that activate PPARγ, which include the thiazolidinedione (TZD) insulin-sensitizing agents used to manage type 2 diabetes, display a number of potential anti- atherogenic properties, including effects on high-density lipoprotein (HDL)-cholesterol and triglycerides, as well as other beneficial non-lipid effects, such as regulating levels of mediators involved in inflammation and endothelial dysfunction. Data from several sources suggest that simple strategies combining TZDs and statins could have complementary effects on CVD risk factors profiles in diabetes, alongside the ability to control glycaemia.

Conclusion: It is hoped that studies currently underway will provide insights into the value of such treatment approaches in terms of reducing the excess CVD risk, morbidity and mortality associated with type 2 diabetes.

Introduction

Coronary heart disease (CHD) and other forms of cardiovascular disease (CVD) are the major cause of mortality in type 2 diabetes1,’2, as well as a major contributor to morbidity and lifetime costs3,4. Risks of incident CHD or fatal CHD are 2-4 fold higher in people with diabetes than in those without5-9. Furthermore, long-term prognosis after a coronary event is significantly worse among people with diabetes than those without10.

Patients with type 2 diabetes (but without previous myocardial infarction) have as high a risk of myocardial infarction as nondiabetic patients with previous myocardial infarction5. Accordingly, the National Cholesterol Education Program (NCEP) guidelines classify diabetes as a CHD ‘risk equivalent1 – a disorder that carries an absolute, 10-year risk for developing new major coronary events equal to that of nondiabetic persons with established CHD (i.e. > 20%)11.

Thus, diabetes is considered an important cause of CVD and, from the perspective of cardiovascular medicine, may even be considered as a CVD in itself12. However, the core metabolic defect in diabetes (i.e. hyperglycaemia) does not by itself raise the risk to the level of a CHD risk equivalent – it is a constellation of metabolic risk factors that combine with hyperglycaemia to impart a high risk11. This review describes the various CVD risk markers presenting in people with type 2 diabetes and highlights how current and potential future strategies aim to reduce CVD risk. It is based on MEDLINE and EMBASE literature searches, conducted between 1994 and 2004, using the search terms metabolic syndrome, type 2 diabetes AND cardiovascular risk markers, endothelial dysfunction, inflammation, dyslipidaemia and atherosclerosis.

Insulin resistance, the metabolic syndrome and cardiovascular disease

A number of discrete CVD risk factors often cluster together in individuals (Table 1) and are closely associated with the presence of insulin resistance, which may be the common etiological factor, although the connection is not fully understood11,13. This combination of multiple CVD risk factors and insulin resistance is collectively known as the ‘metabolic syndrome’ (as defined by the World Health Organization and the NCEP Adult Treatment Panel III11,13 (Table 2). The risk factors (which may not all be present), include impaired glucose regulation, abdominal obesity, hypertension, atherogenic dyslipidaemia (characterized by elevated levels of triglycerides and low levels of high-density lipoprotein [HDL] cholesterol), microalbuminuria and specific proinflammatory and prothrombotic abnormalities of endothelial cell and vascular function11,13-15. In those with normal glucose tolerance, the presence of the metabolic syndrome also predicts a high risk for developing type 2 diabetes13,16,17.

Although each component of the metabolic syndrome conveys an increased CVD risk, the effect is enhanced when in combination. As such, the metabolic syndrome is associated with a 3-fold increase in the risk of CHD and stroke and a 3-fold increase in the likelihood of death from CHD18,19. Furthermore, the risk of CVD (and also diabetes) increases as the number of components of the metabolic syndrome increases16.

The prevalence rate of the metabolic syndrome is high in many Western countries, with 25-35% of the general population affected. On the basis of 2002 census data, approximately 47 million US residents have the metabolic syndrome and age-adjusted prevalence of the metabolic syndrome is 24% in the USA, increasing with age from 7% in National Health and Nutrition Examination Survey (NHANES) III participants aged 20-29 years to 44% in those aged 60-69 years20. The association with diabetes is highlighted in a recent analysis from NHANES III where approximately 85% of people with diabetes were classified as having the metabolic syndrome compared with only 12% of those with normal fasting glucose21.

Type 2 diabetes – an array of cardiovascular risk factors

Dyslipidaemia is an established risk factor for CHD in patients with type 2 diabetes, as well as in non-diabetic patients, and is likely to play a leading role in the increased CVD risk associated with diabetes11,22,23. Many patients with type 2 diabetes and/or the metabolic syndrome typically show a characteristic atherogenic dyslipidaemia, including hypertriglyceridaemia, elevated levels of apolipoprotein B, increased prevalence of small dense low-density lipoprotein (LDL)-cholesterol and low levels of HDL- cholesterol24,25. In addition to these established dyslipidaemic risk factors, patients with type 2 diabetes and those who are insulin resistant are more likely to have small, dense LDL particles. This LDL component is probably atherogenic due to a high susceptibility to oxidation and its presence is an independent risk factor for CVD26. In addition to these ‘traditional’ CVD risk factors, analyses from NHANES III recently highlighted a number of ‘non-traditional’ risk factors that occurred significantly more frequently in diabetes, including high white blood cell count, low serum albumin, low glomerular filtration rate, high plasma fibrinogen and elevated C-reactive protein (CRP)21. Furthermore, 12% of people with diabetes had ≥ 3 non-traditional risk factors compared with only 5% of those with normal fasting glucose.

Table 1. Coronary heart disease risk factors

Table 2. National Cholesterol Education Program (NCEP) and World Health Organization (WHO) definitions of the metabolic syndrome

Large-scale intervention trials highlight the impact of dyslipidaemia in diabetes. For instance, in the United Kingdom Prospective Diabetes Study (UKPDS), there were significant associations between increased risk of CHD and increased concentrations of LDL-cholesterol and triglycerides and decreased concentrations of HDL-cholesterol27. The Diabetes Intervention Study and the Paris Prospective Study found that triglycerides, in particular, were significant predictors of mortality from CHD28,29.

Endothelial dysfunction is generally defined as poor vasodilatory capacity when the effects of vasoconstrictors outweigh the effects of vasodilators30,31. It is a predictor of CVD and is associated with other markers of vascular disease (e.g., CRP, plasminogen activator inhibitor-1 [PAI-1], adiponectin and tumour necrosis factor-α [TNF-α])31,32. It can be detected early in the prediabetic state and the progression of endothelial dysfunction to atherosclerosis parallels that of insulin resistance to type 2 diabetes30,31.

There is a close association between inflammation and endothelial dysfunction and there is increasing evidence that low-grade inflammation, perhaps reflecting a widespread activation of the innate immune system, is closely involved in the pathogenesis of type 2 diabetes, dyslipidaemia and atherosclerosis33. This on-going acute-phase response (seen in insulin resistant subjects and type 2 diabetes patients) is induced by cytokines, and is reflected in elevated circulating inflammatory markers, such as CRP, interleukin (IL)-1, IL-6, TNF-α, leptin, PAI-1, angiotensinogen and fibrinogen (described by Hsueh and Bruemmer34 as a ‘proinflammatory milieu’).

Such chronic inflammation of the endothelial cell and vascular environment impairs endothelium dependent vasodilation, induces the expression of cell-surface adhesion molecules by endothelial cells and in\creases cardiovascular risk35-37. In particular, CRP may play a significant role as it amplifies the inflammatory response by stimulating the production of TNF-α and IL-1 by tissue macrophages37. As such, CRP has been linked with CHD mortality and the development of diabetes33,38,39. CRP also stimulates PAI-1, which inhibits fibrinolysis and also predicts CHD and diabetes, as well as contributing to the prothrombotic state in obesity34,37. The relationship between micro- or macroalbuminuria and CVD mortality may also be related to its association with endothelial dysfunction40,41.

Hyperglycaemia is likely to contribute further to endothelial dysfunction once diabetes develops and poor glycaemic control is a significant predictor of CVD mortality in diabetes11,31,40. Although hyperglycaemia is an established CVD risk factor independent of dyslipidaemia, clinical trials, such as the UKPDS, have not been able to demonstrate definitively that an intensive glucose-lowering policy reduces CHD events11,42,43. Thus, a focus on reducing glycaemia alone does not appear sufficient to reduce the excess risk in diabetes, highlighting the need for aggressive treatment of other risk factors. Some oral agents (e.g., thiazolidinediones [TZDs]) used to treat hyperglycaemia do significantly modify cardiovascular risk factors other than hyperglycaemia44 and may have a role in reducing the CVD burden of diabetes.

PPARγ and cardiovascular risk markers

Activation of peroxisome proliferators-activated receptors (PPAR) γ has profound effects on the myocardium and major cells of the vasculature31,34,45,46 (Figure 1). Firstly, PPARγ ligands inhibit inflammation directly in vascular cells, as well as indirectly through regulation of gene expression in adipose tissue34. They also block vascular smooth muscle cell growth and migration in human atheroma, migration of monocytes and also promote reverse cholesterol transport46. PPARγ ligands also inhibit endothelial cell growth and movement, thus demonstrating anti- angiogenic properties34.

At present, information is not available regarding the long-term effects of PPARγ activation on CVD risk and diabetic complications. However, a number of clinical studies have shown that TZDs (activators of PPARγ), in addition to improving glycaemic control, also exert numerous nonglycaemic effects in patients with type 2 diabetes and may have the potential to improve cardiovascular outcome in type 2 diabetes26,47-52. By improving many of the metabolic and cardiovascular pathways influenced by insulin activity, TZD therapy results in improvements in lipid abnormalities, vascular and coagulation defects, blood pressure and also β-cell function37,53-55.

PPARγ activation – effects on lipid profile

The TZD pioglitazone, in particular, has beneficial effects on lipid profiles in patients with type 2 diabetes, including increased HDL-cholesterol and lowered triglycerides56-67. Moreover, a more direct assessment of the anti-atherogenic effects of pioglitazone has shown that the composition of lipid subfractions also improves with pioglitazone therapy, with reduced concentrations of atherogenic small, dense LDL particles in patients with type 2 diabetes68,69.

Figure 1. Effects of PPARγ ligands on the vasculature and endothelium

These effects on lipid abnormalities may not be a class effect of TZDs; as pioglitazone and rosiglitazone have distinct effects on lipoprotein metabolism, which may have important clinical implications for cardiovascular risk reduction in patients with type 2 diabetes. In a retrospective study from primary care practices, pioglitazone demonstrated significantly greater benefits on blood lipid parameters (triglycerides, total cholesterol and LDL- cholesterol) relative to rosiglitazone, while glycaemic control (as measured by HbA^sub 1c^) was comparable70. Furthermore, recent results from a randomized, prospective, double-blind study comparing the two agents showed that, relative to rosiglitazone, pioglitazone significantly improved triglycerides, HDL-cholesterol and LDL particle concentration and size71. Non-HDL-cholesterol remained stable with pioglitazone, but increased with rosiglitazone.

PPARγ activation – effects on other cardiovascular risk factors

Patients with type 2 diabetes treated with TZDs have shown improvements in other non-lipid cardiovascular risk markers, either directly by affecting vascular smooth walls and cells involved in the atherogenic process or indirectly by improving insulin sensitivity. Markers of inflammation, coagulation and thrombosis, blood pressure and urinary albumin/creatinine ratio (a measure of microalbuminuria) have all been improved with TZD therapy. Both rosiglitazone and pioglitazone significantly improved the albumin/ creatinine ratio, accompanied by reductions in blood pressure, in patients with type 2 diabetes compared with comparator oral agents72,73. Reductions in diastolic blood pressure have also been reported with pioglitazone in non-diabetic patients with arterial hypertension74.

In patients with type 2 diabetes, TZDs (rosiglitazone or pioglitazone) have been shown to reduce CRP levels independent of any effect on glycaemia75,76. A recent study by Pampanelli et al.77, showed that 6-12 months of pioglitazone therapy also significantly improved coagulation and thrombosis parameters in patients with type 2 diabetes independent of glucose control – platelets, von Willebrand factor (vWF; a marker of endothelial dysfunction) and PAI- 1 were reduced, whereas antithrombin III (AT-III) and fibrinogen were increased. No significant changes were seen in a gliclazide comparator group and between-group differences were significant for vWF, PAI-1 and AT-III. Satoh et al.76 also demonstrated that 3 months of pioglitazone therapy significantly reduced pulse wave velocity (a marker of vascular damage and also a predictor of mortality in diabetes). Furthermore, in a study by Koshiyama et al.78, pioglitazone decreased the carotid arterial intima-media wall thickness (an early sign of atherosclerotic change) in patients with type 2 diabetes.

Use of statins in type 2. diabetes and prevention of cardiovascular complications

Statins are the recommended first-line therapy for patients with dyslipidaemia11,79. Clinical trials of statins have shown convincingly that they decrease overall mortality and mortality from CHD by one-third, with a similar decrease in risk of non- hemorrhagic stroke and a decrease in all-cause mortality of almost onequarter80. For instance, the Scandinavian Simvastatin Survival Study (4S) showed that simvastatin therapy reduced CHD events by 55% in people with diabetes81. Pooled data from the Cholesterol and Recurrent Events (CARE) and Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) studies of pravastatin therapy also revealed significantly reduced CHD events in people with diabetes82. The Collaborative Atorvastatin Diabetes Study (CARDS) was halted 2 years early, since patients on statin therapy had significant reductions in acute coronary events by 36% and stroke by 48%83.

While the American College of Physicians has recommended the widespread use of statin therapy to prevent CVD in patients with type 2 diabetes84,85, not all clinicians agree that statins should be used in all patients with type 2 diabetes86. Although statins are effective at lowering LDL-cholesterol (by approximately 20-25%) their effects on triglycerides and HDL-cholesterol are less impressive, with approximately 10-15% decreases in triglycerides and only approximately 5% increases in HDL-cholesterol, and a substantial ‘residual’ cardiovascular risk may remain without appropriate attention to these risk factors80,87-90.

Potential of TZDs as add-on therapy to statins

One novel therapeutic approach to reduce CVD risk in type 2 diabetes may be to use lower-dose statins in combination with TZDs. This has the potential to target multiple cardiovascular risk factors, while also treating the primary symptom of hyperglycaemia. As described above, TZDs produce changes in several cardiovascular risk factors associated with the insulin resistance syndrome, including correcting diabetic dyslipidaemia, improving fibrinolysis and decreasing carotid artery intima-medial thickness26 and, as such, TZD therapy provides a novel approach in the prevention of cardiovascular complications in patients with type 2 diabetes.

Whereas statins produce a marked reduction in LDL-cholesterol and a moderate reduction in triglycerides, with a slight increase in HDL- cholesterol80, pioglitazone has a particularly beneficial effect on triglycerides and HDL-cholesterol. Although TZDs increase LDL- cholesterol, they induce a favourable change in the LDL particle size and susceptibility to oxidation as shown for troglitazone by Tack et al.91. This has been confirmed more recently for pioglitazone in non-diabetic patients with hypertension (in whom the prevalence of atherogenic dense LDL is similar to that in patients with type 2 diabetes), as well as in patients with type 2 diabetes68,69,92. These qualitative changes may have a beneficial effect on cardiovascular risk profile and compensate for a small increase in LDL-cholesterol. Therefore, statins and pioglitazone would appear to have complementary effects on lipid profiles, suggesting a rationale for their use in combination therapy. A recent study by Lewin et al.93 provides strong support for this rationale – low-dose simvastatin addition to stable pioglitazone or rosiglitazone therapy (pooled data) resulted in improvements in all lipid parameters measured, including LDL-cholesterol.

TZDs also have beneficial effects on other markers of cardiovascular risk, which suggest that combination statin/TZD therapy could address the multiple aspects of diabetic dyslipidaemia, as well as having the potential to reduce the incidence of macrovascular events \further. Recently presented data indicate that pioglitazone and simvastatin may act synergistically to lower levels of inflammatory cytokines, including IL-6 and CRP, as well as optimizing patients’ lipid profiles94.

The innovative Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) is currently assessing the effect of pioglitazone on the secondary prevention of macrovascular events in patients with type 2 diabetes who have a history of macrovascular disease and are at high risk of further macrovascular events95. In this study, pioglitazone is being used as ‘add-on’ therapy to current treatment, which is continuously optimized throughout the trial to allow patients to receive the best possible therapy. One- third of patients enrolled were at high vascular risk based on HDL- cholesterol (32.6%) or triglyceride (36.0%) levels, whereas two- thirds were at risk based on raised systolic and/or diastolic blood pressure, and, at baseline, half of the patients were taking lipid- lowering medication (with 42.9% of all patients on statins). It is anticipated that this study will provide important insights into the potential benefits of statin and TZD co-therapy.

Conclusions

It is clear from the data currently available that insulin resistance, the metabolic syndrome and type 2 diabetes are inextricably linked with CVD, as apparent from the increased levels of CVD morbidity and mortality and from the presence of a complex array of CVD risk markers. Targeting multiple markers of CVD risk hopefully offers the best chance of improving CVD outcomes. It is clear that TZDs, and pioglitazone in particular, can provide cardiovascular benefits extending beyond improvements in glucose levels, and probably beyond improvements in lipid profiles. Ongoing studies should generate important insights into whether pioglitazone can play a larger role in the management of CVD, the metabolic syndrome and type 2 diabetes, especially in high-risk cardiovascular patients with diabetes mellitus.

Acknowledgements

I am a member of the Steering Committee of the PROactive study and have received research grants, as well as honoraria for educational presentations, from Bayer (Germany), Takeda Europe R & D, Merck, Sharp and Dohme, Pfizer and Aventis.

I would like to thank Takeda for supporting this supplement with an educational grant. The views presented in this article are entirely my own and have not been influenced in any way by Takeda, nor has Takeda been involved in its preparation.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2863B_5, Accepted for publication: 04 February 2005

Published Online: 07 March 2005

doi: 10.1185/030079905X36459

E. Erdmann

Department of Cardiology, University of Cologne, Germany

Address for correspondence: Prof. Dr. med. Erland Erdmann, Klinik III fr Innere Medizin der Universitt zu Kln, Joseph-Stelzmann-Str. 9, D-50924 Kln, Germany. Tel.: +49-221-478-4503; Fax: +49-221-478- 6275; email: erland.erdmann@uni-koeln.de

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