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Lipid-Lowering Drugs
   Last updated: 25.08.04
When lifestyle and drug switching strategies aren't enough, how do you deal with with high cholesterol and triglycerides? by Edwin J Bernard
Last month's ATU looked at how supporting and encouraging lifestyle interventions - like stopping smoking, exercising and eating a more heart- and pancreas-friendly diet - and switching to a less atherogenic HAART combination are two of the main ways that clinicians are attempting to manage lipodystrophy's metabolic syndrome, which appears to increase our risks of cardiovascular disease.

But what happens when lifestyle changes and/or drug switching aren't enough to move levels of cholesterol and triglycerides to a range that would reduce the risk?

And what about those people who are unable to switch to a more heart-friendly HAART? When resistance and/or tolerability issues reduce the choice of available drugs, keeping control of viral load is likely to preclude drug-switching strategies, unless there are already high coronary heart disease (CHD) risks due to non modifiable factors, like age or a history of smoking or a family history of cardiovascular disease.

According to the latest US1 and UK2 guidelines, under either of these circumstances, lipid-lowering drugs should be used.

However, the use of these therapies is not straightforward, since the class of lipid-lowering drugs known as statins can interact with both antiretrovirals and other medications used by people with HIV. The good news is that if interactions can be avoided, these drugs appear to have a similar effect in people with HIV as those without. The bad news, however, is that even in the general population, only a minority of patients treated with lipid-lowering drugs achieve National Cholesterol Education Programme (NCEP) lipid goals3.

The British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy include very little guidance on using lipid-lowering therapies, other than warnings about drug interactions (see below). Fortunately, recently published US guidelines provide a detailed analysis of what to use and when to use it.

What to use when high LDL cholesterol is the main problem
Normal levels of LDL cholesterol are considered to be 3.5-6.5 mmol/L. The US guidelines make HMG-CoA reductase inhibitors - otherwise known as statins - the first choice for attempting to lower LDL cholesterol that is above this range. Statins lower cholesterol by slowing down the body's production of cholesterol and by increasing the liver's ability to remove the LDL cholesterol already in the blood. They have been used extensively in HIV-negative people to both reduce the risk of CHD in people who have not yet had a cardiovascular event, and also to reduce the progression of CHD in people who have already had a heart attack.

Statins have also been studied in HIV-positive people and although significant toxicities were not reported in these trials, few people actually had clinically significant reductions in their LDL cholesterol levels.

Nevertheless, the US guidelines suggest that when LDL cholesterol or non-HDL cholesterol is elevated, but triglyceride levels are no higher than 5.65 mmol/L (twice the upper level of normal) the two recommended statins to use are either:
  • pravastatin (20-40 mg daily as a starting dose) or

  • atorvastatin (10 mg daily as a starting dose).


At the recent Ninth European AIDS Conference in Warsaw, a team from London's Chelsea & Westminster Hospital presented a paper comparing these two cholesterol-lowering drugs in people on both PI- and NNRTI-based HAART.4 Out of 179 people (102 on atorvastatin and 77 on pravastatin) 82% had a modest decrease in LDL cholesterol: a mean of 1.26 mmol/L on atorvastatin and 1.30 mmol/L on pravastatin. However, 56% of those on atorvastatin managed to decrease their LDL cholesterol levels to below 6.6 mmol/L compared with 32% of those on pravastatin, suggesting that atorvastatin is somewhat more effective.

In this study, the two drugs did not appear to affect people on PIs or NNRTIs differently, but a second paper presented in Warsaw did see a short-term time-dependent difference between those on PI- and NNRTI-based HAART. In this Spanish study5 86 individuals, 60% of whom were on NNRTI-based HAART, were prescribed pravastatin (20 mg/day) for a year. After four months, the people on NNRTI-based HAART appeared to do better than the people in the PI arm with LDL reductions of 21% and 11%, respectively (p=0.05). But after eight months this difference had disappeared, in fact the PI-treated group showed a trend towards greaterLDL cholesterol reduction (-36 vs -25% p=0.008). After eight months, 40% of those in the study achieved NCEP goals. One in five were stepped up to a higher dose of pravastatin (40 mg/day) after the fourth month, however, and pravastatin therapy was stopped in 6% due to what the study's authors euphemistically term "unremarkable side effects", which means no serious muscle or liver toxicity occurred.

The US guidelines also suggest other options to the two recommended statins, noting that fluvostatin (20-40 mg/daily) is a "reasonable alternative." They add that if statins cannot be used - e.g. due to drug-drug interactions - then another class of drugs, fibrates, might be considered (see below).

Since it has been estimated that it will take five or six years to accumulate a clinical benefit from the use of statins in people with a risk of CHD due to high LDL cholesterol, it is probably never too early to start if you are at risk.

When statins or fibrates alone aren't enough
The US guidelines suggest that if statin therapy has not reduced elevated LDL cholesterol, adding either a fibrate or niacin (see below) is a possible approach, but due to the risk of myopathy, statin-fibrate therapy should be used with great caution.

If statins and fibrates are to be used together, the US guidelines recommend pravastatin or fluvostatin in combination with either gemfibrozil or micronised fenofibrate. Additionally, since niacin treatment is associated with an increased risk of insulin resistance, regular fasting glucose levels should be taken.

If fibrate therapy has not reduced elevated triglycerides, the guidelines suggest adding a fish oil supplement (see below) or niacin. Adding statin therapy is not recommended.

What to use when high triglycerides are the main problem
People with HAART-related metabolic disorders tend not to have high triglycerides without also having elevated LDL cholesterol. Sometimes, however, LDL can just be on the wrong side of the upper limit of normal and under these circumstances - when triglyceride levels are above 5.65 mmol/L - then fibrate therapy should be used. Fibrates work in several ways, the main effect being to reduce VLDL (very low density lipoproteins) in the blood which are largely made up of triglycerides. The two recommended drugs are gemfibrozil (600 mg/twice daily, 30 mins. before meals) or micronised fenofibrate (54-160 mg/daily).

An Italian study published in the journal AIDS earlier this year6 compared fibrates with statins for the treatment of hypertriglyceridaemia. One of three different fibrates (bezafibrate, gemfibrozil or fenofibrate) or one of two statins (pravastatin or fluvastatin) were given to 113 PI-based HAART recipients with high triglycerides for a year. Since the numbers on each were small - between 18 and 25 on any one drug - the conclusions reached were no surprise: the fibrates were more effective at reducing triglyceride levels.

Several studies published last year7 found that both gemfibrozil and fenofibrate not only reduced triglyceride levels but also raised HDL ("good") cholesterol levels. However, only a minority of those enrolled in these trials actually achieved normal levels of these beneficial lipids.

Is there a role for more natural therapies?
Niacin - also known as vitamin B3 or nicotinic acid – ought to be a really useful supplement for treating high lipid levels. Not only does it raise HDL cholesterol but it also lowers LDL cholesterol and triglycerides. The problem, however, is that as well as causing flushing - a sort of intense, itchy tingling in the skin - it can induce insulin resistance. Since insulin resistance is already commonly seen in many people with metabolic syndrome, that would be counterproductive. However, a study published three years ago8 concluded that niacin was safe to use in people with diabetes, although glucose levels were still increased by niacin by an average of 0.4 mmol/L in those with, and 0.3 mmol/L in those without, diabetes. The US guidelines, therefore, sensibly suggest that niacin should be avoided as first-line therapy for treatment of high lipids if on PI-based HAART or suffering from lipoatrophy, but reason that it might be useful in some cases.

The amino acid L-carnitine may also reduce triglyceride levels but so far only one small study has been published.9 This open-label, single arm study found that 3 grammes daily (that's six 500 mg tablets) of L-carnitine resulted in a 35% reduction in mean triglyceride levels after an average of nine months, with 40% achieving normal levels (<2.3 mmol/L) and 69% near-normal (<3 mmol/L) levels.

As discussed in last month's article on diet and lipodystrophy, omega-3 fatty acids - found mainly in oily fish - appear to be quite effective in reducing triglyceride levels. If you can't bring yourself to add fish to your diet on a regular basis, you can also buy or be prescribed fish oil capsules. Be aware, however, that you have to take around six a day to get enough omega-3 fatty acid to have an effect.

Drug-drug interactions
The latest BHIVA guidelines place their focus squarely on the possible interactions between statins and PIs. They agree with the US guidelines that the use of simvastatin and lovastatin in people on PI- or delavirdine-containing HAART is not recommended.

  • Atorvastatin levels could be doubled in people on PIs, but both suggest that this drug can be used with caution.


  • Pravastatin appears to be safe with PIs, but whereas the UK guidelines say it appears to have a low likelihood of PI interactions, the US guidelines caution that pravastatin doses may need to be increased when taken along with ritonavir-containing regimens.


  • Fluvastatin does not appear to have any PI-related drug-drug interactions.


  • Any of the statins are probably safe in efavirenz or nevirapine-containing regimens.


  • The US guidelines also suggest that levels of fibrates may be reduced in ritonavir-containing regimens, but otherwise no interactions are known at this time.


Key Conclusions
Lipid-lowering medications can be used instead of, or in addition to, lifestyle changes and/or drug-switching.

Statins - particularly pravastatin and atorvastatin - are relatively safe and somewhat effective in reducing high LDL cholesterol levels, but interactions can occur with some PIs.

Fibrates - usually fenofibrate or gemfibrozil - are used to reduce high triglyceride levels when high LDL cholesterol is not the main concern. They appear to have no significant interactions with PIs.

NNRTIs can be used with any fibrate or statin therapy.

Statins and fibrates should only be used together with great caution. UK guidelines suggest a specialist lipidologist oversee this type of treatment.

Niacin, fish oil and possibly L-carnitine can also be used to lower lipids, but niacin can increase the risk of insulin resistance, and should be used with great caution.

Few people on HAART actually achieve clinically important changes in their lipid profile on these drugs over the short term, and this lipid-lowering therapy should therefore be considered to be a long-term risk-reduction strategy.

References
1. Dube MP et al. CID 37, 2003.
2. www.bhiva.org/guidelines/2003/hiv/index.html
3. www.nhlbi.nih.gov/guidelines/cholesterol
4. Smith N et al. 9th EACS, Warsaw, abs 9.2/3, 2003.
5 Blanco F et al. 9th EACS Warsaw, abs LB9.2/11, 2003.
6. Calza L et al. AIDS 17: 851-859, 2003.
7. Aberg JA et al. 14th Int AIDS Conf, abs LbPeB 9018, 2002; Palacios R et al. JAIDS 51: 251-3, 2002; Miller J et al. AIDS 16: 2195-200, 2002.
8. Elam MB et al. JAMA 284:1263-1270, 2000.
9. Loignon M et al. AIDS 15: 1194-5, 2001.