Therapeutic management of triglycerides: An international perspective

Therapeutic Management of Triglycerides: An International Perspective Thomas A. Pearson,

Current recommendations from varkus International expert committees generally concur in their definlDons of borderline and hlgh triglyceride levels, wlth small but Important differences between recommendations In the deflnltkm of normal levels. However, populatlon-based data on trlglycerkle levels are poorly developed In most countries, making dlflicult any lntematlonal comparSsonsofprevalencesofhypertrlglycerklemla uslng the new definltlons. However, it ls probable that there should be consklerable dtfferewes In the prevalence of hypertrlglycerklemia, probably due to a mbcture ofgenetlc and environmental Influences. The management of hypertrlglycerklemla must continue to emphasize the detection and correctii of secondary causes, even though the speclflc secondary causes may vary between countries. Dietary and exercise interventlons must deal wlth local customs and resources, includlllg striking International dtfferences In alcohol consumption. Pharmacologic therapies will likely Increase in use if they follow the trends In countries with available data. Although various drugs are available, nk%tlnR acid and Rbrk ackl derlvatlves remain the drugs of choice. Consklerably more research Is needed to describe these International differences in etlology, prevalence and management practices of hypertrlgiycerldemla. (Am J Cardlol1662;70:26H4lH)

From the Mary Imogene Bassett Research Institute, Cooperstown, and Columbia University, New York, New York. Address for reprints: Thomas A. Pearson, MD, PhD, The Mary Imogene Bassett Research Institute, 1 Atwell Road, Cooperstown, New York 13326.

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he increasingly recognized role of triglyceride-rich lipoproteins in atherogenesis has led to new recommendations for identification and management of elevated serum triglycerides, including new, lower action limits for fasting triglyceride levels. l-’ These new recommendations, put forth by a panel of international experts from the lipid metabolism field, are potentially useful to physicians of all countries where atherosclerotic disease is the main cause of mortality. The impact of these recommendations, however, will differ from country to country, just as current recommendations for hypertriglyceridemia treatment differ among countries. Further, the magnitude of atherosclerotic risk posed by elevated triglycerides may vary among nations because of differences in gene frequencies and environmental exposures. Management of hypertriglyceridemia may also vary because of differences in secondary causes, local dietary customs, and limited availability of triglyceride-lowering drugs. These and other related issues are the focus of this review. CURRENT RECOMMENDAllONS REGARDING DEFlNl’RONS AND TREATMEN OF HYPERR?IGl.YCERIDEMlA

During the mid-to-late 198Os, expert committees were convened from various professional groups interested in hyperlipidemia and atherosclerosis prevention to recommend definitions and management plans for hypertriglyceridemia.2-6 Some committees discussed only hypertriglyceridemia2; others discussed all lipid disorders, including those dealing with triglycerides.34 Their recommendations for the definition of borderline and high triglyceride levels are consistent (Table I), with a rather narrow range of triglyceride levels used for definition of normal and high. Most also identified the risk of pancreatitis at even higher levels, although this varied from committee to committee. Although the range of definitions of normal triglyceride levels is small, these minimal changes in cutpoints translate into large differences in prevalence of borderline levels, given the distribuDECEMBER

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tion of triglycerides in the typical European or North American population. For example, the difference in prevalence of “abnormal” triglyceride levels using a cutpoint of >2.3 mmol/liter versus that of >2.8 mmol/liter in 40-59-year old U.S. white males would be approximately 20% versus lo%, respectively (Figure 1).8Changing the cutpoint for high triglycerides from 5.6 to 4.5 mmol/liter would have a relatively smaller impact on the number of persons entering treatment. Most recommendations emphasized examining triglyceride levels in the context of the entire lipid profile, including low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels. Although dietary therapies were consistently advocated, enthusiasm for drug therapy varied considerably.

TABLE I Definitions of Normal, Borderline, and High Fasting i Serum Triglyceride Levels: Recommendations of Various Expert Panels Serum Triglycerides (mmol/liter)

Borderline (diet)

High (drug therapy possible*)

Expert Committee

Normal (no therapy)

U.S. Consensus Conference,

c2.9

2.8-5.6

> 5.6

~2.3

2.3-5.6

> 5.6

c3.0

3.0-6.0

>6.0

19842 European Atherosclerosis Society, 19873.4 British Hyperlipidaemia ciation, 19875

Asso-

Canadian Consensus Conference, 1988’3

~2.3

International Committee,

~2.3

~2.3 2.3-4.5

>4.5

1991’ *After failure of diet. tFor adults > 30 years of age.

INTERNATIONAL DIFFERENCES IN THE PREVALENCE OF HYPERTRlGLYCERlDEMlA

ously affecting the prevalence of remnant hyperlipidemia and possibly other lipid disorders. Other There are few data about the prevalence of genetic hypertriglyceridemias, although unstudied, hypertriglyceridemia in various countries. In many might contribute to an increased prevalence of large international studies, serum triglycerides were elevated triglycerides in specific populations. not routinely obtained or fasting sampleswere not Acquired hypertrlglycerldemlas: Numerous required.9 Moreover, the association of triglyceride factors, including metabolic conditions, dietary levels to age and gender would require the careful constituents, and therapeutic drug regimens, have matching of comparison groups (Figure 2). The been identified as potential causes of elevated prevalence of hypertriglyceridemia in white males obviously increases dramatically in middle age. 100 However, the likelihood that there would be sub90 stantial differences in the prevalences of hypertriglyceridemia between countries is great, since com80 parisons of subgroups even within a country show substantial differences. For example, blacks in the 70 United States have lower serum triglyceride levels than whites, especially men (Table II).8 Thus, z 60 substantially more white males than other race and sex groups would be identified as borderline or high by the newly proposed definition of hypertriglyceridemia. Genetic: hypertriicerldemias: Several genetic forms of hypertriglyceridemias have been identified (Table III).‘O At least 2 of these disor20 ders, familial combined hyperlipidemia” and familI I ial dyslipidemic hypertension,12are common, each 10 : affecting 2 15% of patients with coronary artery /I diseaseor hypertension. .’ 0 I I I I I I Specific gene polymorphisms have been linked 3.4 4.0 4.5 1.7 2.3 2.8 0.56 1.1 to several of these disorders; most have not been described at the molecular level. Polymorphisms of Plasma Triglyceride (mmol/L) apoprotein E are a good example of the genetic basisfor a hyperlipidemia (i.e., remnant hyperlipid- ORE 1. Q,~~offasu~plasmat~-,a%ed-9 emia) that might have considerable international, @ycddelevelslnwhttemenand Y-&y(~~----@=eMudy interracial, and interethnic variations (Table IV).13 pennlsslon--upM The E2 polymorphism varies at least 2-fold, obvi- Resemih~lhks.~

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TABLE II Mean and 90th Percentiles for Fasting Plasma Triglyceride Levels in Middle-Aged Whites Versus Blacks in the Lipid Research Clinics Prevalence Study of North America (Visit 1)

I

Plasma Triglycerides (mmol/liter)

I

Men

Mean

90th Percentile

Age (yr)

Race

Women

Mean

90th Percentile

30-34

Whites

1.4

2.4

1.0

1.6

30-39

Blacks

1.2

1.9

0.9

1.5

40-44 40-49

Whites

1.7

1.9

1.4

2.8 2.4

1.2

Blacks

1.1

1.7

ReprIntedwith permlssion from the LIpId ResearchCl~mcs.~

TABLE Ill Primary (Genetic) Focus of Hvpertrinlyceridemia Chylomicronemia

(type I)

Type V hyperlipoprotememla Hepatic triglyceride lipase deficiency Remnant hyperlipidemia

(type III)

Familial hypertriglyceridemia Familial combined hyperlipidemia Hypertriglyceridemia

in high-density lipoprotein deficiency

Familial dysliptdemic hypertension Reprmtedwith permission from Assmann and Brewer.‘o

TABLE IV Apoprotein E (Ape E) Allele Frequencies and Mean Cholesterol Levels in 3 Populations

I

Finland

Germany

Japan

Mean cholesterol (mmol/liter)

ReprIntedwith permlsslon from IntJ Epidemiol.‘3

I

White Males

serum triglyceride levels (Table V). Many are common, with known variations between countries. For example, the prevalence of obesity varies markedly from country to country.14 A male with a I body mass index of 28 kg/m* is at the 90th I percentile in Beijing but at the 50th percentile in Kaunas, Lithuania. Thus, the increased prevalence I of obesity in certain regions might be logically expected to predispose those populations to hypertriglyceridemia. Similarly, populations prone to diabetes might be predicted to have higher prevalences of elevated triglyceride levels. A country’s national diet, including alcoholic beverage consumption, is often an important definition of the culture. However, the amount of fat (especially saturated fat) contributes to both obesity and hypertriglyceridemia. The international variation in the amount and sources of fat is considerable, suggesting that societies with high fat consumption may have higher triglyceride levels (Figure 3). l3 Conversely, societies in which most of the fat comes from fish might be expected to have low triglyceride levels. Few dietary constituents vary as much as alcohol consumption. l4 The relation of alcohol to serum triglycerides has been well described and may constitute a gene-environment interaction in some persons.15 Thus we might expect to find lower 1 triglyceride levels in Norway than in France, with its 24-fold higher wine consumption. Finally, various pharmacologic agents, including 0 blockers, thiazides, and retinoids, affect serum triglyceride levels. Female sex hormones, specifically estrogens (Table VI),s are the most widely I used agents with potent triglyceride effects. The

White Females (Total)

3.2 2.7 2.3

RGURE 2. Means and se4wted

percentleaoffastlngplasmatrlglycarlda lavela In whRe males andfemalesbyageIntheUpld ResearchCllnksPrevalence stuay ollslt 1). (Adapted with permlsslon from the Upld Research Cllnks.~

10

20

30

40

50

60

70+

10

20

30

40

70

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prevalence of triglyceride levels > 2.3 mmol/liter in women using sex hormones exceeds10% at ages >40 years, whereas these levels are much less common in nonusers. Of course, postmenopausal estrogen use has been associated with a 30-50% reduction in coronary risk. Although these triglyceride elevations would not be associated with risk, they would still be identified in any screening program involving serum triglyceride levels. TRIGLYCERIDES

FIGURE 3. Trends from selected

tweml901and198SIngrams -n+umedperpe-P-day.

(Reprlntedwlthpermlssionfrom Int J E/Men~fol.~)

Metabolic conditions Diabetes mellitus Obesity Hypothyroidism

Nephrotic syndrome Renal failure Paraproteinemias

Dietary factors Fat and saturated fat Simple sugars Alcohol Drugs Estrogens Beta blockers

Retinoids Thiazides

I

Treatment ofsocondary causes: The first step in the management of hypertriglyceridemia is the identification and correction of secondary causes (Table V). Just as the prevalence of diabetes, hypothyroidism, nephrotic syndrome, renal failure, and paraproteinemias differs between countries, the prioritization of testing may also change. However, consideration of all these causes and simple testing for these conditions should be standard practice in all countries. Nonpharmacologic therapy: Attaining ideal body weight is the cornerstone of nonpharmacologic therapy for hypertriglyceridemia. Obviously, the high prevalence of obesity in some societies may tax even the most well-equipped health care system, particularly since weight management is often characterized by high labor input and high failure rates. Nonetheless, caloric restrictionsespecially restriction of fat and simple sugarsshould be universally recommended. However, a program of safe physical activity to accelerate caloric expenditure is also necessary.The availability of nutritional counseling servicesand the necessity for physical activity influences how easily obesity can be controlled. Reducing saturated fat input is recommended as part of a prudent diet and will affect triglyceride levels. Again, local dietary customs and each na-

countriesintheconsumptlonof animal and vegetable fats be-

TABLE V Acquired Forms of Hypertriglyceridemia

Fat Consumption/ Day/Person (9)

180

-

160

-

140

-

120

-

TABLE VI Fasting Plasma Triglyceride Levels in White Women Using Sex Hormones Versus White Women Not Using Sex Hormones Plasma Triglycerides (mmol/liter) Users

Age (yr)

Mean

Nonusers

90th Percentile

Mean

90th Percentile 1.3

20-24

1.2

1.7

0.8

30-34

1.3

2.0

0.9

1.4

40-44

1.5

2.3

1.1

1.7

50-54

1.5

2.3

1.3

2.1

60-64

1.4

2.2

1.4

2.3

ReprInted with permission

from the Lipid Research Climcs.8

I

tion’s agricultural sector will influence the availability of sources high in saturated fat. Likewise, the availability of fish high in omega-3 fatty acids will influence triglyceride levels,both as a substitute for foods high in saturated fat and as a foodstuff with direct triglyceride-lowering properties. Finally, controlling alcohol consumption may be easier in some countries than others, depending on the role of wine and beer as daily beverages in some countries versus their role as social beverages in other countries. Pharmacologic therapy. Nicotinic acid and fibric acid derivatives remain the drugs of choice for hypertriglyceridemia. Various forms of niacin cd

Vegetable

o-o

Animal fat

fat

too SO 60

-

40

-

20

-

OPortugal

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higher usage of these agents than the United States. Unfortunately, the agents prescribed and their indications are unknown. However, these differences in levels of prescription may be due Patient Days/100 People Compounded Growth Rate/Year partly to differences in prevalence of hyperlipidCountry 1983 1987 1983-1987 emias, including hypertriglyceridemia. The magniBelgium 99.69 163.72 +13 tude of the differences suggests that local stanCanada 29.01 40.02 +8 dards of medical practice are also a contributing France 653.49 929.42 +9 factor. West Germany 193.94 357.22 +I6 The United States is undergoing a dynamic Italy 138.29 295.28 +21 change in the use of lipid-lowering medications. Spain 74.42 140.81 +17 United Kingdom 13.15 18.09 +8 The rate of increased use of these agents in the United States 25.66 72.34 +30 United States exceeds most other Western coun*Patient-day estimates, which were provided by Warner-Lambert Company, were tries (Table VII). The overall increase in prescripderwd from underlying market research data prwded by 2 market research firms. These firms gave permission to Warner-Lambert Company to make these dewed data tion use has been accompanied by changes in the available for the purpose of this study. Reprinted with permission from Int J Epidemiol. I8 specific agents prescribed (Figure 4).lq Clofibrate dominated the U.S. market in 1978 with 81% of prescriptions, until the World Health Organization are available; it is unknown whether the regular form of niacin versus the slow-release form is used Collaborative Trial,20 which reported increased preferentially in specific countri.es. Various fibric mortality in the clofibrate group, led to a drop in its acid derivatives are available; gemfibrozil is the popularity. Gemfibrozil, however, has greatly increased in dominant form in the U.S. market. Bezafibrate, use since its introduction in 1982, buoyed by the gemfibrozil, fenofibrate, and ciprofibrate are used in Europe and other regions; clofibrate is another findings of the Helsinki Heart Study21 of its safety fibric acid derivative. Bezafibrate, fenofibrate, and and efficacy in reducing cardiac events. The third ciprofibrate appear to have greater LDL cholester- triglyceride-lowering drug, nicotinic acid, has modol-lowering effects than gemfibrozil, but their role erately increased in use, plateauing at a current 8% in the management of hypertriglyceridemia is less of prescriptions (not including over-the-counter well defined.16 3-Hydroq-3-methylglutaryl coen- sales). Few international data are available on the zyme A (HMG-CoA) reductase inhibitors apparcurrent prescribing practices for the specific indicaently are modestly effective in mixed hyperlipidemias17but not in pure hypertriglyceridemias. Fish tion of hypertriglyceridemia. A recent survey of oil supplements should not be considered as pri- prescriptions written in the United States suggests mary drug therapy for hypertriglyceridemia but that gemfibrozil is prescribed in almost 80% of the may be used in daily doses of 12-20 g as adjunct cases of pure hypertriglyceridemia treated with therapy in cases resistant to other agents. drugs (Table VIII; International Marketing SerConsiderable differences exist between coun- vices, New York, New York, unpublished data). tries in their use of lipid-lowering medications Interestingly, approximately 14% of these cases are (Table VII).ls For example, France has a 12-fold prescribed lovastatin, which is not considered a TABLE WI Use of Lipid-Lowering Medications in Patient Days per 100 People per Year and Compounded Growth Rates per Year in 8 Selected Countries*

3,750 3,500 3,250 3,000 2,750 2,500 2,250 2,000

Gemfibrozll .s : : :

Lovastatin

:

l : :,j

Cholestyramine

f -*-

=‘~-“+,,..,I licotinic Acid

V-L-

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FIGURE 4. Esthate4d number of WPrercrlptkn,ofm -tor1979throughl999inthe Unlted9tatesbasedontheNatlonal PresalPtlonAud?t. (ReP--pennisdonJAhW.9

TABLE VIII Drugs Prescribed for Hypertriglyceridemia and for Other Hyperlipidemias in a Survey of United States Pharmacies, March-April 1991

Drug

Hypertriglyceridemia (n = 351) (%)

Other Hyperlipidemias (n = 3,747) (%)

Niacin

5.1

5.9

Slo-Niacin

0.1

0.4

Lovastatin

14.2

35.7

Gemfibrozil

78.1

41.7

Resin

0

10.7

Probucol

2.0

Source of data: International

Marketing

5.6

Services, New York, New York.

first-line drug for this condition. Noteworthy is the lo-fold difference in the number of prescriptions written for other hyperlipidemias. Presumably this consists largely of cases of combined hyperlipidemia and probably reflects the high prevalence of combined hyperlipidemia relative to other lipid disorders. In this category, the leading agents are gemfibrozil and lovastatin, with approximately 42% and 36% of prescriptions, respectively. Niacin constitutes only 5-6%, which almost certainly represents an underestimation because niacin is available over the counter. CONCLUSlON Current recommendations from various international expert committees generally concur in their definitions of borderline and high triglyceride levels, with small but important differences between recommendations in the definition of normal levels. However, population-based data on triglyceride levels are poorly developed in most countries, making difficult any international comparisons of prevalences of hypertriglyceridemia using the new definitions. Thus, the impact of the new recommendations is difficult to gauge on a country-by-country basis. However, it is probable that there should be considerable differences in the prevalence of hypertriglyceridemia, probably due to a mixture of genetic and environmental influences. The management of hypertriglyceridemia must continue to emphasize the detection and correction of secondary causes, even though the specific secondary causes may vary between countries. Dietary and exercise interventions must deal with local customs and resources, including striking international differences in alcohol consumption. Pharmacologic therapies will likely increase in use if they follow the trends in countries with available data. Although various drugs are available, nicotinic acid

and fibric acid derivatives remain the drugs of choice. Considerably more research is needed to describe these international differences in etiology, prevalence, and management practices of hypertriglyceridemia. A worldwide consensus in the definition, detection, and treatment of hypertriglyceridemia would be a major step in refocusing our attention on this potentially important risk factor. REFERENCES l. Assmann G, Gotto AM, Paoletti R. The hypertriglyceridemias: risk and management.Introduction. Am J Car& 1991;68(suppl):lA-4A. 2. National Heart, Lung and Blood Institute ConsensusDevelopment Panel. Treatment of hypertriglyceridemia. JAMA 1984,281:1196-1200. 3. Study Group of the European Atherosclerosis Society. Strategies for the prevention of coronary heart disease: a policy statement of the European AtherosclerosisSociety.Ew Hem J 1987;8:77-88. 4. Study Group of the European Atherosclerosis Society. The recognition and managementof hyperlipidemia in adults: a policy statement of the European AtherosclerosisSociety.Eur Heati .I 1988;9:571a. &Shepherd J, Betteridge DJ, Durrh-@on P, Laker M, Lewis B, Mann J, Miller JP, Reckless JPD, Thompson GR. Strategies for reducing coronaty heart diseaseand desirable limits for blood lipid concentrations:guidelines of the British Hyperlipidaemia Association.Br Med J 1987;295:124>1246. 6. The Canadian ConsensusConference on Cholesterol. Prevention of Heart and Vascular Disease by Altering Serum Cholesterol and Lipoprotein Risk Factors. Final Report. Can MedAssoc .I 1988;139:(suppl):1-8. 7. AssmannG, Betteridge DJ, Gotto AM, Steiner G. Managementof hypertriglyceridemic patients. A. Treatment classifications and goals. Am J Cardiol 1991;68(suppl):30A-3. 8. Lipid ResearchClinics. Population studies data book. Volume I. NIH Publication SC-157.Washington, DC: US Department of Health and Human Services, 1980. 9. World Health Organization MONICA Project. Risk factos. Inf J Epidemiol 1989;18:546-555. 10. Assmann G, Brewer HB Jr. Genetic (primary) forms of hypertriglyceridemia. Am J Cardiol 1991;68(suppl):13A-16A. 1L Goldstein 31 Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary artery disease.II. Genetic analysisof lipid levels in 176families and delineation of a new inherited disorder, combined hyperlipidemia.J C&n Invest 1973;2:15&1568. 12. Williams RR, Hunt SC, Hopkins PN, Stults BM, Wu LL, Hasstedt SJ, Barlow GK, Stephenson SH, LaIouel JM, Kuida H. Familial dyslipidemic hypertension: evidence from 58 Utah families for a syndrome present in approximately 15% of the patients with essentialhypertension.Jm 1988;259: 3579-3586. l3. Sing CF, Moll PP. Genetics of variability of CHD risk. Int J Epideti~ 1989;18:S183-S195. 14. Epstein FH. The relationship of lifestyle to international trends in CHD. Int J Epidemiol 1989;18(suppl):S2C&S2G9. 15. Steinberg D, Pearson TA, KuUer L. Alcohol and atherosclerosis.Am Intern Med 1991;114:%7-976. 16. Illingworth DR. An overview of lipid-lowering drug. Drugs 1988;36(suppl 3):63-71. 17. Vega GL, Grundy SM. Primary hypertriglyceridemia with borderline high cholesterol and elevated apolipoprotein B concentrations.Comparisonof gemfibrozil vs lovastatin therapy.JAM4 1990;264:275%2763. is. Pearson TA. Influences on CHD incidence and case fatality: medical managementof risk factors. Inf J Epidemiol1989;18(suppI):S217-S222. 19. Wysowski DK, Kennedy DL, Gross TP. Prescribed use of cholesterollowering drug in the United States,1978through 1988.JAM4 1990;263:21852188. 20. Committee of Principal Investigators.WHO cooperative trial on primary prevention of ischemicheart diseasewith clofibrate to lower serum cholesterol. Lancet 1984$6oo604. 2l. Frick MH, Elo 0, Haapa K, Heinonen OP, Heinsahni P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Manttari M, Norola S, Pastemack A, Pilckarainen J, Romo M, Sjoblom T, Nikkila EA. Helsinki Heart Study.N Engl J Med 1987;317:1237-1245.

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