Reduction of inflammatory biomarkers through the use of hyperlipidemia drugs in patients with diabetes

Cardiovascular disease occurs at a higher rate in those with type 2 diabetes than in the general population.¹ Diabetic microvascular complications result in greater morbidity; macrovascular complications, however, including coronary heart disease (CHD), often result in mortality.² The risk of CHD in patients with diabetes is so strong that the National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines consider patients with diabetes to have a risk of cardiovascular disease events equivalent to that of patients without diabetes with established cardiovascular disease.

Cardiovascular disease and diabetes are both associated with elevated levels of inflammatory biomarkers.³ Several of the metabolic abnormalities that characterize diabetes enhance the inflammatory responses involved in atherogenesis and promote plaque instability and rupture. Proinflammatory signaling in patients with diabetes is associated with a prothrombotic state. This includes both hyperaggregability of platelets as well as disruption of fibrinolysis within the vessel walls and atheromas.² Negative effects of diabetes-associated hyperglycemia can also include the activation of platelets to produce increased protein kinase C, decreased production of nitric oxide, formation of oxidant ions, and disruption of the calcium homeostasis that controls aggregation and thromboxane formation. Such harmful changes occurring both within the platelets and endothelium contribute to the increased risk of cardiovascular disease among patients with diabetes.

The role of inflammation in the atherosclerotic disease process (initiation, growth, and complications of the atherosclerotic plaque) has been well described and is thought to be a response to injury.⁴ Injurious factors, which can include hypertension, atherogenic lipoproteins, and hyperglycemia, occur more frequently in patients with diabetes than in those without diabetes.⁵ Along with the adverse effects detectable within the vessel wall, the inflammatory pathophysiologic processes also produce blood markers that are measurable and can be used to monitor inflammatory progression. The most well-studied and validated marker of inflammation is C-reactive protein (CRP). CRP is a nonspecific, chronic marker of systemic inflammation that is produced in the liver in response to inflammatory reactions, especially interleukin-6, and has been shown to predict cardiovascular events.⁶ A new biomarker that has been proposed to be a more precise marker of vascular inflammation is lipoprotein-associated phospholipase A₂ (Lp-PLA₂). Lp-PLA₂ is an enzyme produced by macrophages and other cells involved in the inflammatory process associated with atherosclerotic plaque development.⁷ It has also been shown to independently predict future coronary events.⁷ The key enzymatic role of Lp-PLA₂ in atherogenesis is the hydrolysis of oxidized low-density lipoprotein (LDL) cholesterol within the arterial wall to the proinflammatory products lysophosphatidylcholine and free fatty acids. These by-products lead directly or indirectly to chemoattraction of monocytes, impairment of endothelial function, disruption of plasma membranes causing cell death, and induction of apoptosis in smooth muscle cells and macrophages.⁷

Levels of CRP^8,9 and Lp-PLA₂¹⁰ have been shown to be variably decreased with statin and fibrate treatment. Until recently, little was known regarding the effect of the combination of statin and fibrate therapy on inflammatory biomarkers, including high-sensitivity (hs)CRP, but particularly on Lp-PLA₂. Our group investigated the effect of the combination of simvastatin and fenofibrate on inflammatory biomarkers in patients with type 2 diabetes.¹¹ In this double-blind, placebo-controlled, randomized study of 300 dyslipidemic individuals with type II diabetes, there was a highly significant modification in plasma concentrations of total cholesterol, LDL cholesterol, very low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and non-HDL cholesterol for combination therapy of simvastatin 20 mg and fenofibrate 160 mg when compared to either form of monotherapy. Combination therapy was also effective in improving hsCRP and Lp-PLA₂ levels, but was not superior to either form of monotherapy. HsCRP levels decreased 14% with simvastatin, 16% with fenofibrate, and 15.9% with combination therapy. Lp-PLA₂ levels decreased 26.9% with fenofibrate, 34.5% with simvastatin, and 36.2% with combination therapy. Further, the magnitude of reduction by fenofibrate, simvastatin, and combination therapy was greatest when concentrations of hsCRP and Lp-PLA2 were elevated above 2.0 mg/L and the median value of 320.9 ng/mL, respectively. Koh and colleagues examined the effect of atorvastatin, fenofibrate, and combination therapy on hsCRP levels in patients with hyperlipidemia.¹² As in our study, they found that all therapies decreased hsCRP levels from baseline in a similar manner. They did not evaluate Lp-PLA₂ levels.

It is not clear why combination therapy does not have a greater effect on these inflammatory biomarkers than simvastatin or fenofibrate monotherapy. Although statins and fibrates have different mechanisms of action in relationship to lipid metabolism, it is possible that they both exert a similar non—dose-responsive effect on inflammation. Therefore, combination therapy would have no greater effect than monotherapy.

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It has been previously reported that a statin's reduction of LDL-C in patients with type II diabetes may be the main mechanism by which statins reduce Lp-PLA₂ levels.¹³ However, in our study, a decrease in LDL cholesterol only weakly correlated with a reduction in Lp-PLA₂ levels (r = 0.35; < .001).¹¹ The exact mechanisms and effects by which statins and fibrates alter hsCRP and Lp-PLA₂ concentrations remain unknown. Whether these effects can affect the long-term cardiovascular outcome of patients with diabetes also remains to be determined.

In addition to inflammatory effects, diabetes is also associated with a form of atherogenic dyslipidemia characterized by hypertriglyceridemia, low HDL cholesterol levels, and increased levels of small, dense LDL cholesterol. Both statins⁸ and fibrates¹⁴ have been shown, independently, to improve lipoprotein metabolism and decrease coronary risk. However, each affects different aspects of lipoprotein metabolism, and thereby may have a complementary effect when used in combination. Generally, statins lower total cholesterol and LDL cholesterol, whereas fibrates decrease triglyceride concentrations and elevate HDL cholesterol. Since individual lipid parameters have been shown to be independent cardiovascular risk factors, it may be important to target them all. For this reason, the NCEP guidelines have set separate targets for each.¹⁵ Our study showed that combination therapy had a greater overall effect than either form of monotherapy in improving all lipid parameters and was the most effective at reaching goal for the NCEP targets (LDL cholesterol < 100 mg/dL; HDL cholesterol > 40 mg/dL; and triglycerides, < 150 mg/dL).

Both the lipid-related and inflammatory abnormalities associated with type 2 diabetes independently potentiate atherogenesis, thrombosis, and inflammation and thus increase the risk of cardiovascular disease and subsequent cardiovascular events. In our study, the combination of fenofibrate and simvastatin more effectively improved the entire lipid profile, including LDL cholesterol, HDL cholesterol, and triglycerides than either form of monotherapy. Combination therapy also significantly lowered the inflammatory markers hsCRP and Lp-PLA₂, with these effects being most pronounced among patients with increased baseline inflammatory markers. It is interesting to note, however, that combination therapy was no more effective than either form of monotherapy in lowering either hsCRP or Lp-PLA₂.

Conclusions

With its superior effect on lipid parameters and its positive effect on inflammatory markers, combination therapy with both a statin and a fibrate may well be the treatment of choice among patients with mixed dyslipidemia and type 2 diabetes. This possibility is further strengthened by the strong association between concomitant reductions in lipids (LDL cholesterol < 70 mg/dL), inflammatory markers (hsCRP < 2 mg/L), and cardiovascular risk, as demonstrated in studies such as the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial.⁸ It may be that the ability to adequately decrease inflammatory levels while controlling atherogenic dyslipidemia in patients with diabetes is critical. However, whether combination therapy more effectively reduces long-term cardiovascular risk is yet to be determined in large outcomes trials. This question is currently being assessed in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.¹⁶