December 2004, Vol 26, No. 12
Update Articles

Management of hyperlipidaemia in elderly

L P Lui 呂聯彬, K S Ho 何健生

HK Pract 2004;26:520-526

Summary

Hyperlipidaemia is common in the elderly population. About 17.9% of elderly people in Hong Kong older than age 60 are diagnosed to have hyperlipidaemia. Hypercholesterolaemia is an independent modifiable risk factor for coronary heart disease in elderly patients aged below 80. However, the routine screening of hyperlipidaemia in elderly patients is still debatable. Dietary therapy and exercise can improve the lipoprotein profile. Also, Statins have been shown to be beneficial for secondary prevention of coronary heart disease. The safety and effectiveness of other lipid-lowering agents are not well established especially for the older population. Although statins are safe for elderly people, a more cautious approach should be adopted for the primary prevention of coronary heart disease, particularly for octogenarians.

摘要

高齡人仕中，高血脂非常普遍。香港60歲以上老人約17.9%有高血脂。80歲以下老人，高膽固醇血症是一項獨立的，可以改變的心血管病危險因素。是否施行常規血脂普查，目前仍有很大爭議性。飲食治療和運動可以改善血脂情況。現已證明Statins對心血管病的二期預防有效，儘管Statin的安全性好，但對心血管病的一期預防，特別是對80歲以上的病人，還是要謹慎使用。而其他降血脂藥物對老年病人的安全性和有效性還不太確定。

Introduction

In Hong Kong, coronary heart disease is the second leading cause of death, which contributes 15.8% of all death in people older than the age of 65.1 About 17.9% of elderly people older than age 60 are known to have hyperlipidaemia and it is the fifth most common chronic disease in the elderly population.2 The management of hyperlipidaemia for the prevention of cardiovascular disease is well established for middle-aged patients, but there are still some controversies about its efficacy for the older patients. This article reviews the recent clinical trials conducted to study the effect of hyperlipidaemia management in elderly patients.

Physiology of hyperlipidaemia in elderly

The high prevalence of hyperlipidaemia in elderly is related to hormonal changes.3,4 The LDL cholesterol levels tend to increase progressively after puberty and plateau at age of 60.5 With aging, there is a decrease in intrahepatic disposal of the cholesterol. The number of hepatic LDL receptor decreases and the bile acid synthesis declines. Animal studies also show that with aging the cholesterol is absorbed from the intestine more efficiently and the feedback inhibition of cholesterol synthesis is impaired.5

Hyperlipidaemia and coronary heart disease in elderly

Hypercholesterolaemia is an independent modifiable risk factor for coronary heart disease in elderly aged below 80. In the Established Population for the Epidemiological Study of the Elderly (EPESE) trial6 which included participants with mean age of near 80, elevated total cholesterol levels were associated with a significant increase in the risk of death from coronary heart disease (RR 1.57) after adjusting for other coronary risk factors and markers for frailty. In the Laiser Permanente Coronary Heart Disease in the Elderly Study7 involving a cohort of men aged 60 to 79; the attributable risk of hypercholesterolaemia increased five fold with increasing age, from 2.2 deaths per 1000 person-years at age of 60 to 11.3 after the age of 75. In addition, in a meta-analysis of 22 cohort studies, researchers find that total cholesterol and LDL cholesterol levels are significantly correlated with fatal coronary heart disease in both men and women, including patients older than 65 years of age but younger than 80.8

The importance of hypercholesterolaemia as a coronary heart disease risk factor is not clear in patients aged more than 80. In Framingham Heart Study,9 it was reported that the relative risk of high cholesterol levels decreased as age increased and a significant inverse relationship appeared at the age of 80. In the Leiden 85- Plus Study10 involving 324 patients aged more than 85 years, there was no association between total cholesterol levels and coronary heart disease deaths. There are conflicting data to support hypertriglyceridaemia as an independent risk factor for coronary heart disease in the elderly.11,12

Screening of hyperlipidaemia in elderly

There is little direct evidence about the benefits or burdens of screening in the elderly people. Recent meta-analysis does not provide good evidence to support the role of lipid lowering therapy in primary prevention of coronary heart disease in elderly.13 The average age of subjects in the major trials of primary prevention was less than 60.13 Therefore, the routine screening of hyperlipidaemia in elderly is debatable. The US Public Service Task Force and the American College of Physicians14 advice against screening individuals aged 75 or older. Although the National Cholesterol Education Program15 does not set an upper age limit for lipid screening, it recommends caution in proceeding to drug therapy in the elderly for primary prevention.

Non-pharmacological intervention

Diet

Dietary therapy can reduce the total cholesterol levels by 5-20 % and the LDL cholesterol levels by 6-21%.16-20 However, it is difficult to achieve a drastic change in diet that are required to lower cholesterol levels below the level commonly associated with atherosclerosis. The American Heart Association (AHA) Nutrition Committee recommends both saturated fat and trans-fatty acid intake should be limited to less than 10% of total daily intake calories. The cholesterol consumption should be less than 200 milligram per day for those with high LDL cholesterol levels and patients with cardiovascular disease.15 Eating fiber supplements or oat products can lower the total and LDL cholesterol levels. Replacing foods high in saturated fat with those foods containing polyunsaturated fat21 e.g. nuts, flaxseed oil, and substituting animal protein with soy product in the diet22 can lower the LDL cholesterol levels. Researchers also find that an increase in the consumption of fruits and vegetables, and limiting sugar and alcohol intakes can lower the triglyceride level and increase the HDL cholesterol level.23,24 However, only a few of these studies include elderly people and their effects, efficacy in the elderly are still uncertain. When prescribing dietary intervention in elderly, use of dietitian or specialized dietary counselling services should be encouraged to avoid problem of malnutrition.

Exercise

Exercise can improve lipoprotein profile in elderly. Studies show that elderly people that follow regular, high-intensity exercise routine have significantly higher HDL cholesterol levels, lower triglyceride levels and a lower total/HDL cholesterol ratio than those performing lower intensity exercise.25 However, some studies found that exercise without weight loss may not have a significant effect in lipid levels, so it is possible that weight loss and not exercise may be responsible for the improvement in lipoprotein profile.26,27

Pharmacological intervention

Statins

The HMG-CoA reductase inhibitor drugs decrease cholesterol synthesis in the liver by competitively inhibiting HMG-CoA reductase. This action induces increased synthesis of hepatic LDL receptors and increases removal of LDL particle from the circulation. They also have beneficial effects which are independent of their effect on lipid profile. Statins can improve endothelial dysfunction, reduce inflammatory component of atherosclerosis progression and decrease platelet aggregation and deposition.28-33 Statins are the most widely used medication for management of hypercholesterolaemia. The large number of clinical data and trials in 1990s leave no doubt that statins have beneficial effect in both primary and secondary prevention of coronary heart disease for patients younger than the age of 65, but how about their role in older patients?

Statins for primary prevention of coronary heart disease

The role of statins in the primary prevention of coronary heart disease in elderly remains controversial.

In the Air Force / Texas Coronary Atherosclerosis Prevention study (AFCAPS/TEXCAPS),34 6,605 men and women aged 45 to 73 with an average coronary risk and a mean serum total cholesterol of 5.7 mmol/L were studied. Participants who were treated with lovastatin had a 29% lower incidence of major coronary event compared with those receiving placebo. The absolute risk reduction of acute major coronary events was 4.1% (p<0.001). Although patients up to 73 years of age were enrolled in the study, this trial did not provide conclusive evidence of benefit from lovastatin for primary prevention of coronary heart disease in patients older than 70 years of age.

In Prospective Study of Pravastatin in Elderly at Risk (PROSPER),35 5,804 men and women aged 70 to 82 (mean age of 75) were recruited. These patients had either preexisting vascular disease (coronary or peripheral) or were at increased risk for vascular diseases such as smoking, pre-existing hypertension or diabetes. At three years follow up, the primary composite end points (CHD related death, nonfatal MI and stroke) were reduced by 15% in the pravastatin group (16.2% vs 14.1%) and the absolute risk reduction was 1.9% (p<0.014). The secondary end points (death from CHD or nonfatal MI) were reduced by 19%. There was no significant difference in the incidence of strokes between the treatment and placebo groups.

In ALLHATLL study,36 10,355 subjects aged 55 years and older with mean age of 66.5 suffering from hypertension and at least one additional coronary risk factor were included. The LDL cholesterol levels varied from 3.1 mmol/L to 4.9 mmol/L. Pravastatin 40 mg/day was given with a follow up of 4.8 years. There was no reduction in all-cause mortality or coronary heart disease in this study compared with the placebo group.

Statins for secondary prevention of coronary heart disease

Several studies demonstrated the benefits of statins in the elderly with established coronary heart disease. In the subgroup analysis of Scandinavian Simvastatin Survival Study (4S),37 elderly patients older than 65 years with high cholesterol levels and coronary heart disease were studied. It showed that simvastatin significantly reduced the total cholesterol levels by 26%, all cause mortality by 30% and coronary heart disease mortality by 38%.

The Long term Intervention with Pravastatin in Ischaemic Disease study (LIPID)38 also confirmed the importance of statins in secondary prevention of coronary heart disease. In this trial, pravastain was given to elderly patients aged 65-75 with history of myocardial infarction or unstable angina and elevated cholesterol levels. The result showed that pravastatin led to 18% reduction in total cholesterol levels, 22 % reduction in all-cause mortality, 24% reduction in death from coronary heart disease, and 29% reduction in fatal and nonfatal myocardial infarction.

In Heart Protection Study (HPS),39 20,536 patients (aged 40-80 years) with 5,806 aged at least 70 years were recruited. These patients suffered from coronary heart diseases, other occlusive arterial diseases, diabetes or treated hypertension, and had total serum cholesterol levels of at least 3.5 mmol/L. Simvastatin reduced the coronary mortality by 18% and all cause mortality by 17%. The absolute risk on total mortality was reduced by 1.8% (p<0.0003); vascular deaths reduced by 1.5% (p<0.0001); strokes reduced by 1.4% (p<0.001).

The benefits of statins are also shown in patients with average cholesterol levels. In the Cholesterol And Recurrent Event trial (CARE),40 1283 elderly patients older than 65 with average cholesterol levels and recent myocardial infarction were studied. It was proved that pravastatin reduced the total cholesterol levels by 20% and the incidence of cardiac death or nonfatal myocardial infarction by 32%; the stroke rate also declined by 40%.

The results of all these studies clearly indicate that the benefits of statins therapy in secondary prevention among middle-aged adults can be extended to elderly patients older than age of 70.

Other lipid-lowering agents

The effectiveness of bile acid sequestrants, fibrate and nicotinic acid are not well established in the elderly patients because most of the trials do not involve elderly patients older than the age of 70.

Bile acid sequestrants

Bile acid sequestrants act by binding bile acids in the intestine in order to interrupt the enterohepatic circulation of bile acids and increase the conversion of cholesterol into bile acids in the liver.

In the Lipid Research Clinic Coronary Primary Prevention Trial,41 3806 asymptomatic men aged 35 to 69 years were studied. Cholestyramine reduced the coronary heart disease death and definite non-fatal myocardial infarction by 19%. Although the bile acid sequestrants are not commonly used as the first line treatment nowadays, they can be added if statins fail to reduce the cholesterol levels. Bile acid sequestrants do not increase the incidence of myositis in patients taking statins.42

Fibrate

Fibrate reduces blood levels of VLDL, triglyceride by inhibiting VLDL production in the liver and by enhancing the clearance of VLDL from the circulation. It also raises HDL cholesterol levels by its stimulation of VLDL catabolism.

In Veterans Affairs High density Lipoprotein Cholesterol Intervention Trial, (VA-HIT).43 2531 men of mean age of 64 suffering from coronary heart disease with low HDL cholesterol levels and hypertriglyceridaemia were recruited. Gemfibrozil did not change the mean serum LDL cholesterol levels; however, it reduced significantly the mean serum total cholesterol levels by 4%, mean serum triglyceride by 31% and increased the mean serum HDL cholesterol levels by 6%. There was also 26% risk reduction in combined end points of coronary heart disease death, non-fatal myocardial infarction and stroke.

On the other hand, in Bezafibrate Infarction Prevention study,44 3090 patients of mean age of 60 with coronary heart disease but no hypertriglyceridaemia were studied. Bezafibrate caused 18% increase in serum HDL cholesterol levels and 21% reduction in serum triglyceride levels, but it failed to reduce the primary end points of fatal or nonfatal myocardial infarction or sudden death significantly.

Since there is no definite evidence showing that treatment of hypertriglyceridaemia in absence of increase LDL cholesterol levels or decrease HDL cholesterol levels will reduce the incidence of cardiovascular disease, fibrate is mainly used to treat hypertriglycerdaemia with serum triglyceride levels higher than 500 mg/dl to prevent pancreatitis.21 It may also have a role when primary lipid abnormality is a low serum HDL cholesterol levels.

Nicotinic acid

Nicotinic acid lowers cholesterol and triglyceride levels by decreasing the hepatic secretion of VLDLs and lowering of the plasma concentration of free fatty acid. According to Stockholm Ischaemic Heart Disease Secondary Prevention Study,45 it has been shown effective in combination with clofibrate to reduce the progression of coronary atherosclerosis.

Safety of pharmacological intervention

The results of Cholesterol Reduction in Seniors Progress (CRISP) pilot study46 showed that there was no significance difference in symptoms, side effects and score of any health related quality of life measures between those taking lovastatin or placebo. Recent reviews on clinical safety of statins also suggest that statins are well tolerated to patients older than 70 and there is no increase in laboratory test abnormalities and side effects.47-49 However, the narrow therapeutic window of most drugs in the elderly patients, co-morbid illness and polypharmacy make the elderly become a group of high risk for complication of therapy. Therefore, cautious use of drugs and regular monitoring of side effects are important. There are also conflicting evidences suggesting that statins may increase the risk of cancer.35,38,39 The safety of other lipid-lowering agents are not well established in the elderly population.

Discussion on pharmacological intervention

There are controversies on the need for aggressive management of hyperlipidaemia in elderly patients. For primary prevention of coronary heart disease, the role of lipid lowering therapy in people older than age of 70 is uncertain, particularly in the low risk group.34-36 There is also no good evidence suggesting that cholesterol levels are associated with coronary heart disease in elderly older than age of 80.6-12 In addition, both Framingham Heart Study19 and Honolulu Heart Program50 showed a U-shaped distribution between the risk of death and total cholesterol levels in elderly patients. The low concentration of serum cholesterol predicted an increase in mortality. Therefore, a more cautious approach should be adopted in this age group. The use of lipid lowering therapy in the elderly should be based on patient' s preference and overall risk of coronary heart disease before treatment.

For secondary prevention of coronary heart disease, several studies have demonstrated that statins reduce the risk of recurrent coronary heart disease in elderly patients.35,37-40 The benefits of the statins observed among middle aged adult can be extended to include elderly patients older than age of 70. The cost effectiveness of statins for secondary prevention of coronary heart disease in elderly has also been established.51

Kumana CR et al52 had gauged the impact of statins drug using number needed to treat (NNT). They remarked that values for NNT (and NNT per year) differed dramatically in different studies. Among 4S patients (with both CHD and hypercholesterolaemia) the NNT for 1 year was an estimated 63 persons to prevent a simple coronary event. Among AFCAPS/TexCAPS participants (with neither CHD nor hypercholesterolaemia) the NNT per year was 256. In CARE study (CHD only), NNT was 167 whereas in WOSCOP study (hypercholesterolaemia without CHD), the corresponding NNT was 217. A recent meta-analysis13 shows that the average age of subjects in the major trial of primary prevention is less than 60 years and that 250 people need to be treated for 5 years to prevent 1 death. In addition, the study concludes that treatment with lipid lowering drugs lasting 5.7 years does not reduce all-cause mortality in people with no known cardiovascular disease. In the presence of increasing medical cost nowadays, it is reasonable to spend our health care resource in a more cost effective way. Although statins have been shown to be effective in reducing the cholesterol level and major coronary events, emphasis should be put on the overall assessment, therapeutic life style changes and management of other risk factors predisposing to cardiovascular disease.

Conclusion

Hyperlipidaemia is common in elderly and is a major risk factor for coronary heart disease in elderly up to age of 80. However the routine screening of hyperlipidaemia in elderly is still controversial. Although statins have been shown to be effective in reducing the cholesterol level and major coronary events, emphasis should be put on the overall assessment, therapeutic life style changes and management of other risk factors predisposing to cardiovascular disease. Various studies have established that elderly patients with coronary heart disease are benefited from statins therapy. As for primary prevention, it appears that statins may be beneficial to the high risk groups up to age of 70. However, these studies are overseas studies, which involve mainly white population. The guidelines on management of hypercholesterolaemia are essentially based on these studies and epidemiological data such as the Framingham model. Some guidelines only include patients up to the age of 70, e.g. Sheffield table for coronary and cardiovascular risk estimation for primary prevention. An updated clinical guideline and a similar risk assessment model are very much needed in Hong Kong.

Key messages

  1. In Hong Kong, 17.9% of elderly aged 60 or above are known to have hyperlipidaemia.
  2. The high prevalence of hyperlipidaemia in elderly is related to hormonal changes and the decrease in intrahepatic disposal of the cholesterol.
  3. Hypercholesterolaemia is an independent modifiable risk factor for coronary heart disease in elderly aged below 80. For hypertriglyceridaemia, there is conflicting data to support whether it is an independent risk factor for coronary heart disease.
  4. The routine screening of hyperlipidaemia in elderly is still debatable.
  5. Dietary therapy and exercise can improve the lipoprotein profile.
  6. Statins have been shown to be beneficial for secondary prevention of coronary heart disease and appeared to be beneficial in primary prevention in high risk group up to the age of 70. The effectiveness of other lipid-lowering agents is not well established in elderly.
  7. Statins are safe for elderly, but a more conservative approach should be adopted in this age group.

L P Lui, MBChB(CUHK), FRACGP, FHKCFP, FHKAM(Fam Med)
Medical Officer,

K S Ho, MBBS(HK), FHKAM(Medicne), FHKAM(Fam Med)
Consultant,
Elderly Health Services, Department of Health HKSAR.

Correspondence to : Dr L P Lui, Tsuen Wan Elderly Health Centre, G/F, Lady Trench Polyclinic, 213 Sha Tsui Road, NT, Hong Kong.

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