How can we manage diabetic dyslipidaemia to reduce cardiovascular risk?

HDL Forum Editor Professor Philip Barter discusses the options available to clinicians for treating atherogenic diabetic dyslipidaemia. This commentary was based on a lecture on Diabetes and Cardiovascular risk on Dave.md

Cardiovascular complications pose the greatest disease burden in type 2 diabetes. The majority of patients will die as a result of these complications. Even when patients manage to achieve good glycaemic control, the risk of cardiovascular disease remains high.1,2

One of the main factors responsible for this increased cardiovascular risk is the lipid profile typically associated with type 2 diabetes. This profile is characterised by elevated triglyceride-rich lipoproteins (very low-density lipoproteins [VLDL] and their remnants) and a low level of high-density lipoprotein (HDL) cholesterol. In addition, while levels of low-density lipoprotein (LDL) cholesterol may be normal or only modestly elevated, there is an increase in the number of small, dense LDL particles, which are thought to be highly atherogenic because of their increased susceptibility to oxidation and their greater ability to penetrate the arterial wall.3 This profile is commonly referred to as the lipid triad. Data from the United Kingdom Prospective Diabetes Study show that low HDL cholesterol, a component of the lipid triad, is the second strongest cardiovascular risk factor after LDL cholesterol in patients with diabetes.4

The lipid triad is characteristic of type 2 diabetes

  • Low HDL cholesterol
  • Elevated triglycerides
  • Increase in small, dense LDL particles

Low HDL cholesterol is the second strongest cardiovascular risk factor after LDL cholesterol

Insulin resistance associated with diabetes underlies the development of the lipid triad. Insulin resistance drives the release of free fatty acids (FFAs) from adipose tissue, which turn increases the production of VLDL in the liver. Together with down-regulation of the enzyme lipoprotein lipase, which is involved in the breakdown of triglyceride-rich VLDL to FFAs, these changes promote a net increase in triglyceride levels. Additionally, cholesterol ester transfer protein (CETP) plays a key role in the development of the lipid triad. CETP promotes the exchange of triglyceride for cholesteryl ester in LDL, resulting in the formation of triglyceride-rich cholesteryl ester-depleted LDL, which subsequently undergo hydrolysis leading to an increase in small, dense LDL particles. In addition, CETP-mediated exchange of triglyceride for cholesteryl ester in HDL favours the production of triglyceride-rich small, dense HDL with reduced anti-inflammatory and anti-oxidant properties. These smaller HDL particles are more rapidly broken down and cleared by the kidney, further reducing plasma levels of HDL cholesterol.

Life style interventions, such increased physical activity, a low-fat diet and stopping smoking, clearly have a role as a first step in improving diabetic dyslipidaemia. However, most patients will also require pharmacological therapy.

Lifestyle interventions
  • Increased physical activity
  • Stopping smoking
  • Losing weight
  • Low-fat diet

Statins currently represent the cornerstone of dyslipidaemia management in diabetic patients in primary and secondary settings, based on their efficacy in reducing cardiovascular risk by lowering LDL cholesterol. In the secondary prevention setting, data from the Heart Protection study (HPS), the largest statin study to date, which included a subgroup of 5,963 patients with diabetes (29% of the total study group) with or at high risk of cardiovascular disease, showed the outcome benefits of statin therapy. Among this cohort, treatment with simvastatin 40 mg/day reduced by 22% the risk of first major vascular event (non-fatal myocardial infarction [MI], coronary heart disease (CHD) death, stroke and revascularisation).5 Studies such as the Collaborative Atorvastatin Diabetes Study (CARDS) have also shown that statins are effective in reducing cardiovascular risk in the primary prevention setting.6 It is worth noting, however, that results from the Atorvastatin Study for the Prevention of coronary heart disease Endpoints in Non-insulin dependent diabetes mellitus (ASPEN), which was predominantly a primary prevention study, were inconclusive.7

Despite treatment with an efficacious dose of statin, the residual risk of further cardiovascular events in diabetic patients remains high. Even aggressive lowering of LDL cholesterol to below target levels fails to adequately reduce this risk. In the Treating to New Targets (TNT) study, the level of cardiovascular risk reduction amongst a cohort of 1,501 diabetic patients (15% of the total study population) was of similar magnitude to that demonstrated overall (25% vs. 22% relative risk reduction).8 These data indicate that we need to target abnormalities that define the diabetic lipid triad, to further reduce this risk. Suitable pharmacological approaches that may be considered include the addition of a fibrate or nicotinic acid.

Fibrates are effective against all components of the lipid triad, raising HDL cholesterol by 5-15%, lowering triglycerides (by up to 50%) and promoting a shift from small, dense to larger, more buoyant (and hence less atherogenic) LDL particles.9

Admittedly there are fewer well-designed clinical trials with fibrates than statins to support their efficacy in reducing cardiovascular risk in patients with diabetes. Subgroup analyses from the Veterans Affairs HDL Intervention Trial (VA-HIT) demonstrated the efficacy of the fibrate gemfibrozil in reducing cardiovascular risk in a cohort of patients with diabetes (30% of the total study population) and CHD. There was a significant 32% relative risk reduction in the composite endpoint of CHD death, MI and stroke (p=0.004), compared with 18% relative risk reduction in non-diabetic patients (versus 24% relative risk reduction in the total study population, p<0.0001).10

More recently, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, which included 9,795 patients with type 2 diabetes (78% with no prior cardiovascular disease) investigated the potential benefits of fenofibrate 200 mg/day in this setting. Although there was an 11% reduction in the primary endpoint (non-fatal MI and CHD death), this was not statistically significant. There was, however, a significant reduction in cardiovascular disease events (by 11%, p=0.035). Notably, the effects of fenofibrate on HDL cholesterol observed in FIELD were less than anticipated clinically (increase in HDL cholesterol at study close was about 2%). In part this may be due to the finding that only 38% of patients had evidence of the lipid triad at entry to the study.11 Thus, the majority of patients enrolled in FIELD would not normally have been considered for dyslipidaemia management in normal clinical practice.

Nicotinic acid is the most potent agent currently available for raising HDL cholesterol, and is also effective against other components of the lipid triad.12 However, we need to await data from the ongoing AIM HIGH study (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes) to evaluate the long-term outcome benefits of this combination treatment in patients with diabetes.13

Effective treatment of the atherogenic dyslipidaemia associated with type 2 diabetes is important in reducing cardiovascular risk. While lifestyle intervention has a role in management, there is also a clear case for using treatment effective against all components of the lipid triad, in addition to a statin, to reduce the residual cardiovascular risk in diabetic patients.

References

1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-53.

2. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.

3. Austin MA, Edwards KL. Small, dense low-density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167-71

4. Turner RC, Millns H, Neil HAW et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23). BMJ 1998;316:823-8

5. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16.

6. Colhoun HM, Betteridge DJ, Durrington PN et al. 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;364:685-96.

7. Knopp RH, D’Emden M, Smilde JG et al. Efficacy and safety of atorvastatin in the prevention of cardiovascular endpoints in subjects with type 2 diabetes. The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN). Diabetes Care 2006 ;29 :1478-85.

8. Shepherd J, Barter P, Carmena R et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 2006;29:1220-6.

9. Chapman MJ. Fibrates in 2003: therapeutic action in atherogenic dyslipidaemia and future perspectives. Atherosclerosis 2003;171:1-13.

10. Rubins HB, Robins SJ, Collins D et al. Diabetes, plasma insulin, and cardiovascular disease. Subgroup analysis from the Department of Veterans Affairs High-density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med 2002;162:2597-604.

11. The FIELD study investigators. Effect of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366:1849-61.

12. McCormack PL, Keating GM. Prolonged-release nicotinic acid. A review of its use in the treatment of dyslipidaemia. Drugs 2005;65:2719-40.

13. Clinical Trial: AIM HIGH: Niacin plus statin to prevent vascular events. Available from www.clinicaltrials.gov.ct Accessed 13 Feb 2006