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Managing CV risk in type 2 diabetes: Towards best practice (Part 1: Lipid-modulating agents)

Roger Gadsby

Type 2 diabetes is a complex disease with multiple complications requiring multiple interventions. The absolute risk of developing cardiovascular disease is two-fold greater in people with type 2 diabetes compared with the general population (Fox et al, 2004). Approximately 80 % of people with type 2 diabetes will die prematurely from cardiovascular (CV) complications (Barnett and O’Gara, 2003). Optimising the management of CV risk in people with type 2 diabetes is therefore essential in order to improve CV morbidity and mortality. This is part 1 of a series of three articles aiming to provide an overview of the multifactorial interventions that, according to evidence-based medicine, can improve cardiovascular morbidity and mortality in type 2 diabetes. In part 1, Roger Gadsby looks at lipid-modulating agents.

There are a number of recognised factors known to contribute to the increased risk of cardiovascular (CV) death associated with type 2 diabetes (Castelli, 1988; Turner et al, 1998): raised low-density lipoprotein (LDL)-cholesterol levels; diabetic dyslipidaemia (reduced high-density lipoprotein [HDL]-cholesterol levels, high triglyceride levels, and the presence of small, dense atherogenic LDL particles); hypertension; insulin resistance; and hyperglycaemia.

The importance of primary care in the management of type 2 diabetes and the associated CV risk factors is reflected in the National Service Framework for diabetes (Department of Health, 2001) and the Quality and Outcomes Framework (QOF) of the new General Medical Services (nGMS) contract, revisions to which took effect from 1 April 2006 (British Medical Association [BMA], 2006; Kenny, 2006). The revised QOF outlines 16 indicators in diabetes and a maximum of 93 points will be awarded according to the percentage of patients that meet these targets (Kenny, 2006). The nGMS contract is centred on three main therapeutic interventions relating to diabetes. It encourages GPs to achieve good glycaemic control (HbA1c ≤7.5%), decrease total cholesterol (to ≤5mmol/l) and decrease blood pressure (to ≤145/85 mmHg) in people with diabetes.

The challenge facing primary care practitioners is to implement the best possible standard of care for people with type 2 diabetes in order to improve outcomes.

To achieve this goal, there needs to be an awareness of the best pharmacological tools currently available, the evidence for which comes from large clinical studies. Evidence-based medicine has highlighted the need for multifactorial interventions in people with type 2 diabetes (Gaede et al, 2003; Donnelly, 2005) and shown that more than one intervention is often required in the management of each risk factor.

Current guidelines for management of lipids in type 2 diabetes
The Joint British Societies’ guidelines on prevention of cardiovascular disease (CVD) in clinical practice (known as JBS 2) have provided guidance on lipid-lowering therapy in diabetes (British Cardiac Society et al, 2005). JBS 2 recommends statin use in all people with diabetes (type 1 or type 2) aged ≥40 years. Statin use is also recommended in younger people with diabetes (18–39 years) with at least one other risk factor, including retinopathy, nephropathy, hypertension and features of the metabolic syndrome. The target lipid levels recommended by JBS 2 are <2 mmol/l for LDL-cholesterol and <4 mmol/l for total cholesterol.

Guidance from the National Institute for Health and Clinical Excellence (NICE; formerly the National Institute for Clinical Excellence) recommends statin therapy for adults with clinical evidence of CVD and for adults who have a 20 % or greater 10-year risk of developing CVD (NICE, 2006). The guidance also highlights the lack of validated risk calculators for people with diabetes, and recommends that risk in each case should be assessed clinically. The lipid targets outlined by NICE are <3 mmol/l for LDL-cholesterol and <5 mmol/l for total cholesterol (NICE, 2002), which are higher than the targets set by JBS 2.

Evidence base for the use of lipid-modulating agents 
As mentioned earlier, the triad of lipid abnormalities characteristic of diabetic dyslipidaemia are reduced HDL-cholesterol levels, high triglyceride levels, and the presence of small, dense LDL particles. People with type 2 diabetes do not tend to have particularly high LDL-cholesterol levels, per se, but there are differences in the qualitative nature of the LDL particle (Syvanne and Taskinen, 1997). Managing these complex lipid disorders is a crucial component of diabetes treatment that can reduce the risk of CV morbidity and mortality (Laakso et al, 1993).

In early prospective studies, increased triglyceride levels and decreased HDL-cholesterol were deemed as more powerful predictors of CVD than LDL-cholesterol in type 2 diabetes (Lehto et al, 1997). On this basis, early guidance (American Diabetes Association, 1993) for the treatment of diabetic dyslipidaemia focused on targeting triglycerides and HDL-cholesterol using fibrates, such as gemfibrozil.

Only in recent years – following the weight of evidence provided by large, randomised clinical trials – has the emphasis been put on LDL-cholesterol-lowering agents (statins) to improve CV outcomes, most recently in type 2 diabetes. Those studies that have to date provided evidence to change treatment practice with regard to lipid modulation in type 2 diabetes are described below and summarised in Tables 1 and 2.

Statins act by lowering LDL-cholesterol levels. Their effectiveness in lowering LDL-cholesterol with the consequent improvement in CV outcome has been well studied and documented, as described below.

Robust evidence for the use of statins comes from the Heart Protection Study (HPS), which included 5963 people with diabetes (Collins et al, 2003). Importantly, the HPS also revealed that cholesterol-lowering therapy produces similar risk reductions for major vascular events regardless of the presence or absence of CVD and regardless of baseline LDL-cholesterol concentrations. The Collaborative AtoRvastatin Diabetes Study (CARDS) exclusively studied people with type 2 diabetes with no documented history of CVD (Colhoun et al, 2004). Consistent with the findings of the HPS, evidence from CARDS suggests that all individuals with type 2 diabetes should be considered for statin therapy irrespective of their baseline LDL-cholesterol concentration.

Fibrates, or peroxisome proliferator-activated receptor (PPAR)-α agonists, target diabetic dyslipidaemia by raising HDL-cholesterol levels and decreasing triglyceride levels. Two studies, the Department of Veterans Affairs High-density lipoprotein Intervention Trial (VA-HIT; Rubins et al, 2002) and the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD; Keech et al, 2005) study, have provided some information on the role of these agents in reducing CV mortality in type 2 diabetes.

It remained unclear from the results of the VA-HIT study whether increases in HDL-cholesterol levels, decreases in triglyceride levels or both were responsible for the beneficial effect on CV outcomes. To address this question in people with type 2 diabetes, the FIELD study was designed (Keech et al, 2005).

The FIELD study results are somewhat disappointing, the author feels, because they do not give a clear answer as to the role of fibrates in tackling diabetic dyslipidaemia. The findings may have been confounded by the fact that significantly more people in the placebo group were allocated a statin during the study than in the fenofibrate group (17 % versus 8 %). It could be that a greater increase in HDL-cholesterol levels is more important in terms of CV outcomes than a decrease in triglyceride levels. Nonetheless, current clinical trial evidence does not warrant an increase in the use of fenofibrate in people with type 2 diabetes (Colhoun, 2005).

Other agents
Niacin, also referred to as ‘nicotinic acid’, is an old therapeutic agent that is very effective at raising HDL-cholesterol levels (Ashen and Blumenthal, 2005). The actions of niacin are associated with unpleasant side effects, most commonly flushing and skin rash as well as more serious hepatotoxicity and dysglycaemia. A prolonged-release formulation of niacin has been shown to minimise some of these side effects (McCormack and Keating, 2005).

Prolonged-release niacin alone was shown in four randomised controlled trials to decrease LDL-cholesterol levels (–13 %), decrease triglycerides levels (–26 %) and increase HDL-cholesterol levels (+18 %; figures in parentheses represent pooled data; Birjmohun et al, 2004). In four comparative cohort studies of prolonged-release niacin in combination with a statin, the combination showed an additional 22 % reduction in LDL-cholesterol and 8 % reduction in triglycerides compared with prolonged-release niacin monotherapy (figures in parentheses represent pooled data; Birjmohun et al, 2004). Statin therapy had a small (1 %) additional effect on a total 25 % increase in HDL-cholesterol during prolonged-release niacin treatment.

Ezetimibe is a novel selective inhibitor of intestinal cholesterol absorption and acts by blocking cholesterol transport across the intestinal wall. Ezetimibe is an effective LDL-cholesterol-lowering agent and its pharmacological effect is complementary to that of the statins (Bays, 2002; Mikhailidis et al, 2005). Trials are ongoing to investigate the effects of ezetimibe in combination with low-dose statin.

Lipid-modulating agents like those described above are designed to target particular aspects of the lipid profile. Therefore, it is noteworthy that some oral hypoglycaemic agents, whose principal role is to lower blood glucose levels, have also been shown to have beneficial effects on lipid parameters in type 2 diabetes. However, not all hypoglycaemic agents have been shown to confer the same beneficial effects.

The thiazolidinediones, or glitazones (pioglitazone and rosiglitazone), are PPAR-γ agonists that act as insulin-sensitising oral hypoglycaemic agents and have been shown to improve key lipid parameters in type 2 diabetes, beyond their glucose-lowering capability (Reynolds and Goldberg, 2006). Significant differences between the glitazones were highlighted in the first head-to-head, randomised controlled study of rosiglitazone and pioglitazone in people with type 2 diabetes and dyslipidaemia (these individuals were not taking any lipid-lowering agents; Goldberg et al, 2005). Pioglitazone was associated with significant decreases in triglycerides, increases in HDL-cholesterol and increases in LDL particle size (from small, dense atherogenic particles to larger, more buoyant and less atherogenic particles) compared with rosiglitazone.

When used as an oral hypoglycaemic agent in conjunction with best available care, including lipid-modulating therapies, pioglitazone may further improve CV outcomes in type 2 diabetes (Dormandy et al, 2005). It is as yet unknown whether these findings are related to an improvement in lipid profile.

By contrast, metformin has no clinically significant effects on total cholesterol, HDL-cholesterol, LDL-cholesterol or triglycerides compared with placebo (Saenz et al, 2006). Furthermore, only sparse data are available on the CV and lipid-related effects of the insulin secretagogues (Buse et al, 2004; Granberry and Fonseca, 2005). An overview comparing the effects of metformin, gliclazide, pioglitazone and rosiglitazone on lipid parameters in type 2 diabetes is shown in Table 3.

Towards best practice
In the author’s opinion, it is now best practice to consider statin therapy for primary prevention in all people with type 2 diabetes and to prescribe one of the two statins that have an evidence base for primary prevention, simvastatin 40 mg daily (HPS) or atorvastatin 10 mg daily (CARDS), unless there is a good reason not to. The evidence base for the use of statins extends to around the age of 80 years. However, trials usually exclude people with significant co-morbidities, and these may be seen in around two-thirds of people over the age of 75 years (Sinclair, 2000). The author feels that the use of statin therapy in people over the age of 80 years therefore needs to be considered on an individual basis.

Statins are generally well tolerated with a well-characterised safety profile. Occasionally abdominal pain and myalgia occur with the currently available agents, rarely raised liver enzymes and myopathy, and extremely rarely rhabdomyolysis (BMA and Royal Pharmaceutical Society of Great Britain, 2006).

If a person does not reach the QOF total cholesterol target (≤5mmol/l) on the maximum-tolerated dose of statin, then fenofibrate, ezetimibe or prolonged-release niacin could be added. These three agents will lower cholesterol but there are, as yet, no studies with hard outcome data that show that lowering cholesterol with a statin in addition to any one of these agents is better than a statin in addition to any other.

Therefore the decision on which agent to add to the maximum-tolerated dose of statin has to be made on consideration of other issues, including price and tolerability.

Current nGMS indicators (BMA, 2006) and NICE guidelines (NICE, 2002) do not reflect the need to tackle the individual components of diabetic dyslipidaemia by providing targets for HDL-cholesterol and triglyceride levels. However, there are currently no outcome data to support interventions that increase HDL-cholesterol or decrease triglyceride levels. Nevertheless, these should not be ignored, the author believes, once statins have been initiated for LDL-cholesterol control.

Future strategies
Evidence from CARDS and the HPS suggests that we treat all individuals with diabetes with statins regardless of their baseline LDL-cholesterol and history of CVD. We need to review current targets for LDL-cholesterol and total cholesterol since evidence encourages treatment of people who are already below these targets. The difficulty is in finding the right targets and the question remains ‘how low do you go?’.

The Atorvastatin in Factorial with Omega-3 fatty acids Risk Reduction in Diabetes (AFORRD) study is a randomised controlled trial assessing the degree to which LDL-cholesterol lowering (with atorvastatin), triglyceride lowering (with omega-3 fatty acids) or both reduces the estimated risk of coronary heart disease in people with type 2 diabetes (Oxford Centre for Diabetes, Endocrinology & Metabolism, 2006). The results of AFORRD, expected in late 2006, will provide insights into the role of triglycerides in the development of coronary heart disease and could potentially provide evidence for triglyceride lowering with omega-3 fatty acids in type 2 diabetes.

There is a need to re-visit agents with HDL-cholesterol-raising or triglyceride-lowering properties. The focus of future treatment strategies, the author believes, should be on agents or combinations of agents that offer a tailored approach to addressing the particular requirements of the diabetic dyslipidaemic profile by treating to target. Such a tailored approach may further improve CV outcomes in this high-risk group of people and this need should also be reflected in future guidelines for the management of diabetic dyslipidaemia.


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