Rudy Bilous, MD, FRCP
Richard Donnelly, MD, PHD, FRCP, FRACP
Dyslipidemia in type 2 diabetes
Abnormalities of blood lipids are common in patients with type 2 diabetes, even when there is reasonable glycemic control. The characteristic dyslipidemia of type 2 diabetes consists of elevated very low-density lipoprotein (VLDL) triglyceride (TG) levels, reduced high-density lipoprotein (HDL) cholesterol and minimal change in total and low-density lipoprotein (LDL) cholesterol concentrations. Overproduction of TG-rich VLDL by the liver and impaired TG clearance by endothelial lipoprotein lipase are contributory factors. Although total and LDL-cholesterol levels in patients with type 2 diabetes are no different from those in subjects without diabetes, the profile of LDL subfractions in patients with type 2 diabetes is more atherogenic due to a greater proportion of small, dense LDL particles (known as the ‘type B’ pattern) which are more susceptible to oxidation; oxidized LDL plays a major role in atherogenesis. Improved glycemic control results in less VLDL-triglyceride synthesis in the liver, but these lipid abnormalities are not completely resolved by lowering HbA1c.
In the German PROCAM study, 39% of patients with type 2 diabetes had fasting serum TG concentrations > 2.3 mmol/L (vs 21% in non-diabetics) and 27% had HDL-cholesterol levels < 0.9 mmol/L (vs 16% in non-diabetics).
The dyslipidemia of type 2 diabetes is frequently accompanied by other metabolic and biochemical abnormalities indicative of insulin resistance, chronic low-grade inflammation (e.g. increased high-sensitivity C-reactive protein (hsCRP) and elevated cytokines such as interleukin-6 and tumor necrosis factor-a) and a prothrombotic state (increased levels of fibrinogen and PAI-1). Collectively, these abnormalities interact to substantially increase the risk of cardiovascular disease (Figure 18.1).
Type 1 diabetes
In non-obese, well-controlled type 1 diabetes, serum lipid and lipoprotein concentrations are similar to those in people without diabetes. In poorly controlled type 1 diabetes, hypertriglyceridemia can occur because insulin deficiency causes increased lipolysis, overproduction of non-esterified fatty acids and VLDL, and decreased activity of endothelial lipoprotein lipase, which reduces clearance of triglyceride-containing VLDL and chylomicrons. Very high triglyceride levels (> 20 mmol/L) can occur in patients with poorly controlled or newly presenting type 1 diabetes, often in association with ketoacidosis. Complications include eruptive xanthomas in the skin (Figure 18.2), acute pancreatitis and lipemia retinalis (a milky appearance of the retinal vessels seen on ophthalmoscopy). The main determinants of hyperlipidemia in type 1 diabetes are age, obesity, poor glycemic control and nephropathy.
Cholesterol as a powerful CV risk factor
The relationship between total cholesterol levels and CHD mortality was first identified in the screening database of male subjects for the Multiple Risk Factor Intervention Trial (MRFIT) (Figure 18.3). Over 360,000 healthy men were screened, and for both subjects with and without diabetes there was a continuous relationship between cholesterol and CHD death rates over the subsequent 10-year period. This observational epidemiology provided evidence for cholesterol as a risk factor, and suggested that, among patients with diabetes, for any given level of cholesterol the CHD mortality was 3 – 4-fold higher.
Statins (HMG-CoA reductase inhibitors) are the drugs of first choice for lowering cholesterol levels and CHD risk, especially in patients with diabetes (Figure 18.4). Examples include simvastatin, rosuvastatin and atorvastatin. They work by inhibiting an early step in cholesterol synthesis, reducing hepatic cholesterol production by up to 50%, which secondarily upregulates LDL receptor synthesis and thus promotes the removal of LDL cholesterol and VLDL remnant particles from the blood. LDL-cholesterol levels fall by up to 50% and triglycerides by about 20%. Second-and third-generation statins are more effective at lowering triglyceride levels. The drugs are generally safe and well tolerated, but generalized muscle aches and pains are more common than previously thought. Myositis is a rare adverse effect, but is more common when statins are used with fibrates, nicotinic acid or cyclosporin.
Evidence-based use of statins
The initial placebo-controlled trials of statins for primary and secondary cardiovascular prevention included only a small proportion of patients with diabetes. Subsequently, the CARDS trial (atorvastatin versus placebo) was undertaken solely in patients with type 2 diabetes (Figure 18.6), and the larger Heart Protection Study (HPS) included approximately 25% of patients with diabetes. These trials have demonstrated that statins have a powerful effect on lowering cardiovascular mortality and morbidity among patients with diabetes, even at relatively low baseline levels of cholesterol, and the relative risk reductions in major CV events are at least as high in diabetics compared with non-diabetics. Most clinical guidelines now recommend statin therapy for all patients with diabetes; target levels of lipids should be a total cholesterol < 4 mmol/L and LDL-cholesterol < 2 mmol/L. Given that most patients have baseline untreated levels of total cholesterol > 6 mmol/L, these targets are often difficult to achieve using standard doses of first-generation statins such as simvastatin 40 mg.
A meta-analysis of cholesterol-lowering therapy in 18,686 patients with diabetes has quantified the risk reductions per 1 mmol/L reduction in LDL-cholesterol. In individual patients, statin therapy will typically reduce LDL-cholesterol by 1 – 2 mmol/L. There is no conclusive evidence that statin therapy prevents diabetes.
Fibric acid derivatives (e.g. fenofibrate) are useful for the treatment of hypertriglyceridemia and mixed hyperlipidemia, lowering serum TG and increasing HDL cholesterol. Their mechanism of action involves binding to the nuclear receptor, peroxisome proliferator activated receptor (PPAR-a), which forms a complex with another nuclear receptor, RXR and modulates several genes that control lipoprotein metabolism (e.g. increasing triglyceride breakdown). Several trials show that fibrates reduce CHD events in diabetes and they appear particularly beneficial in patients with features of the metabolic syndrome. In the ACCORD study, however, combination therapy of fenofibrate and simvastatin did not result in a further lowering of CV mortality in patients with type 2 diabetes compared with simvastatin alone. Only a small subgroup with high TG and low HbA 1c benefitted.
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Rudy Bilous MD, FRCP, Professor of Clinical Medicine, Newcastle University, Honorary Consultant Endocrinologist, South Tees Foundation Trust, Middlesbrough, UK Richard Donnelly MD, PHD, FRCP, FRACP, Head, School of Graduate Entry Medicine and Health, University of Nottingham, Honorary Consultant Physician, Derby Hospitals NHS Foundation Trust, Derby, UK
A John Wiley & Sons, Ltd., Publication This edition first published 2010, © 2010 by Rudy Bilous and Richard Donnelly. Previous editions: 1992, 1999, 2004
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