Diabetic dyslipidaemia explained

Understanding diabetic dyslipidaemia is key to effective treatment, says Dr Brian Crichton.

Diabetic dyslipidaemia is characterised by a predominance of small, dense LDL cholesterol (LDL-C), low HDL-C and raised triglyceride (TG) levels.

As our understanding of its complex pathophysiology has increased, it has become accepted that treating the lipid profile is an effective way of reducing the risk of cardiovascular disease (CVD) and atherosclerosis in patients with diabetic or pre-diabetic dyslipidaemia.

It is important to understand the mechanism behind diabetic dyslipidaemia in order to provide optimal treatment.

Diabetic dyslipidaemia
In the insulin-resistant state of diabetes, there is an increase in the release of free fatty acids (FFAs) from adipose tissue. This stimulates the liver to increase production of large TG-rich, very low-density lipoprotein (VLDL), which promotes hypertriglyceridaemia and activates other enzymes, leading to the creation of small, dense LDL-C and HDL-C particles.

Small, dense LDL-C is prone to oxidation and is highly atherogenic. It is taken up preferentially by macrophages within the blood vessel wall, thereby promoting the growth of foam cells and an atheromatous plaque.

Small, dense HDL-C is rapidly broken down and removed from the plasma, resulting in low levels of HDL-C. This is unfavourable, as normal HDL-C is believed to be responsible for removing excess cholesterol from macrophages, preventing further growth of the atheromatous plaque and inducing regression. It is also thought to protect LDL-C against oxidation.

Statin therapy
The efficacy of statins in reducing LDL-C in all patients, including those with type-2 diabetes, is well established and therefore they should be the first-choice pharmacological intervention.

Statins work by inhibiting the enzyme that catalyses the rate-limiting step in cholesterol biosynthesis. Consequently, statins decrease total cholesterol and LDL-C levels dramatically, but have less potent effects on lowering TGs and raising HDL-C.

The results of the Heart Protection Study (HPS) and Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated that statin therapy is efficacious at preventing cardiovascular events in patients with diabetes, regardless of their LDL-C level.

Based on findings from CARDS, atorvastatin was approved in 2005 by the FDA for reducing the risk of stroke and heart attack in type-2 diabetes patients, near-normal cholesterol and at least one other cardiovascular risk factor.

The Joint British Societies 2 (JBS 2) guidelines recommend that all high-risk patients with diabetes mellitus should be prescribed a statin unless there is a contraindication or tolerability issue.

However, the effect of statins on other components of dyslipidaemia, which also contribute to the increased risk of CVD, are not sufficient to provide optimal control.

Fibrates
Fibrates are agonists of the alpha subclass of the peroxisome proliferator-activated receptors (PPAR), which regulate lipid metabolism. They reduce TGs to a greater extent than statins and increase HDL-C. They also reduce small, dense LDL-C to a lesser degree.

The Veterans Affairs HDL Intervention Trial (VA-HIT) showed that treatment with gemfibrozil was associated with a significant reduction in major cardiovascular events, including CHD-death, stroke or MI, in patients with diabetes and CHD, whose primary lipid abnormality was low HDL-C.

Combination therapy
Combination therapy with a statin and a fibrate in patients with diabetes is being compared with statin therapy alone in the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. This should provide a more definitive answer regarding the safety, including risks of hepatic dysfunction and severe myopathy, efficacy and cardiovascular outcomes of this combination.

Nicotinic acid
Nicotinic acid is probably the most effective available option for raising levels of HDL-C. It also reduces TG levels and increases LDL-C particle size, treating all three features of the lipid triad.

The main drawback of this therapy was tolerability due to flushing symptoms. However, this has been much improved by the production of a modified-release preparation.

Glitazones
There is growing interest concerning the effects of the insulin-sensitising glitazones, pioglitazone and rosiglitazone, on the diabetic dyslipidaemic profile. These drugs activate PPAR.

Pioglitazone has potentially more favourable effects on plasma lipids. A 24-week study showed that pioglitazone reduced TGs by 12 per cent, whereas rosiglitazone increased TGs by 15 per cent. Both drugs increased HDL-C over time, but the increase was greater with pioglitazone than rosiglitazone.

The recent PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study reported a significant 16 per cent reduction in the secondary end point of all-cause mortality, non-fatal MI and stroke with pioglitazone, compared with placebo, in patients with type-2 diabetes at high risk of macrovascular events.

Guidelines
Treatment targets for lipids are now evolving. There are no defined targets within the new GMS contract for TGs and HDL-C. In contrast, the JBS 2 guidelines highlight that HDL-C and TGs are markers for increased cardiovascular risk. In addition, the current NICE guidelines have a recommended target for TGs.

Dr Crichton is a GP trainer and honorary senior clinical lecturer at Hobs Moat Medical Centre, Solihull, Birmingham

Lipid targets in type-2 diabetes

JBS-2 recommends targets of

  • Total cholesterol (TC) <4.0mmol/l.
  • LDL-C <2.0mmol/l.
JBS-2 states the following are markers of increased cardiovascular risk and indications for statin therapy:
  • TC [s40]6.0mmol/l.
  • HDL-C <1.0mmol/l (men) or <1.2mmol/l (women).
  • Fasting TGs >1.7mmol/l (non-fasting >2.0mmol/l).

NICE recommends targets of

  • TC <5.0mmol/l.
  • LDL-C <3.0mmol/l.
  • TGs <2.3mmol/l.

 Diagnosis and treatment
  • Diabetic dyslipidaemia is a cluster of lipid abnormalities characterised by low HDL-C, high TGs and a predominance of small, dense LDL-C, all of which increase the risk of CVD.
  • Many patients with type-2 diabetes and the metabolic syndrome are not receiving the optimal treatment for their dyslipidaemia.
  • Statins are effective in reducing LDL-C; however they are not as effective in correcting other components of dyslipidaemia, which are also associated with an increased risk of CVD.
  • A variety of therapeutic interventions have demonstrated efficacy in improving the individual components of dyslipidaemia, including fibrates, nicotinic acid and some glitazones.
  • The focus of future therapy is on applying drug combination strategies that offer an approach that can be tailored to addressing the macrovascular and microvascular risk factors specific to type-2 diabetes.

 References
 
  • British Cardiac Society, British Hypertension Society, Diabetes UK, Heart UK, Primary Care Cardiovascular Society, The Stroke Association. JBS-2 Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91: v1-52.
  • NICE. Management of type 2 diabetes: management of blood pressure and blood lipids (Guideline H) 2002.

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