Hyperlipidemia is defined as elevated levels of various lipids in the bloodstream. This section will focus on hypercholesterolemia and hypertriglyceridemia, both of which constitute major risk factors for CVDs.
Hypercholesterolemia and Hypertriglyceridemia
Hypercholesterolemia is usually defined by the presence of one, or more of the following lipid abnormalities: elevated total cholesterol (TC) (200-239 mg/dL considered borderline-high risk, or ≥240 mg/dL considered high risk); elevated low-density lipoprotein cholesterol (LDL-C,>130 mg/dL); and elevated non-high density lipoprotein cholesterol (HDL-C, ≥145 mg/dL).4,11,12 Hypertriglyceridemia is a lipid abnormality characterized by elevated serum triglyceride (TG) levels (≥150 mg/dL), and is also a risk factor for CVD.13
According to a 2012 report, 42.2% of US adults are at moderate risk of developing hypercholesterolemia (TC ≥200 mg/dL), 13.1% are at high risk (TC ≥240 mg/dL) (Table 4), and another 6.2% of cases are thought to be undiagnosed.6
|Data source||Population||Category||Prevalence (%)|
|NHANES 2009-2012 (extrapolated for 2012)||US, adults, age ≥20 years||Elevated total cholesterol (TC ≥200 mg/dL)||42.2|
|Hypercholesterolemia (TC ≥240 mg/dL)||13.1|
Source: Mozaffarian et al. 20156
In 2008, a study of over 100,000 medical records of members of Kaiser Permanente Northwest, reported that approximately 36% of US adults presented with TG levels (≥150 mg/dL) that may lead to hypertriglyceridemia (Table 5).
|Data source||Population||Method||Hypertriglyceridemia||Prevalence (%)|
|Members of Kaiser Permanente Northwest, 2008||US, adults (age >e;18 years) (n=108,324)||Observational cohort study of electronic medical records||Borderline-high risk (TG 150-199 mg/dL)||16.4|
|High risk TG 200-499 mg/dL)||18.0|
|Severe hypertriglyceridemia TG ≥500 mg/dL)||1.5|
Source: Nichols et al., 20118
The risk of developing hypercholesterolemia or hypertriglyceridemia is determined by a number of factors, including sex, race/ethnicity, age, weight classification status, education, healthcare, geography, and comorbidities.11,14
Table 6 summarizes data on sex differences in the prevalence of risk factors associated with hypercholesterolemia in US adults, children and adolescents. In brief, when assessing TC levels, females show a higher prevalence of the disease than their male counterparts, independently of age. These sex differences in hypercholesterolemia have been attributed to lower ideal physical activity in females (44%) than males (67%).15 Interestingly, a Minnesota-based study, found the prevalence of hypercholesterolemia (TC ≥200 and ≥240 mg/dL) to be lower in females than males, presumably due to better regional education and healthcare among females.14 On the contrary, males show a higher prevalence of elevated LDL-C and depressed HDL-C levels (Table 6).
Table 6: Sex differences in risk factors associated to hypercholesterolemia the United States.
|Lipid profile||Data source||Population||Lipid level||Prevalence (%)||Reference|
|US, adults, age ≥20 years (n=4,148)
|TC ≥200 mg/dL||50.5||49.7||51.1||Ford et al. 200316|
|TC ≥240 mg/dL||17.8||16.7||18.7|
|NHANES 2011-2012||US, adults, age ≥20 years (n=3469)||TC ≥200 mg/dL||NR||NR||NR||Carroll et al. 201317|
|TC ≥240 mg/dL||12.9||11.1||14.4|
Minnesota Heart Survey (MHS) 2000-2002
|US, adults, age 25-84 years (n=1,352)||TC ≥200 mg/dL||50.0||54.9||46.5||Arnett et al. 200514|
|TC ≥240 mg/dL||20.0||23.9||17.3|
|NHANES 2005-2010||US, children, age 12-19 years (n=4,673)||TC 170-199 mg/dL||25||20||27||Shay et al. 201315|
|TC ≥200 mg/dL||8||8||8|
|NHANES 2011-2012||US children, age 8-17 years (n=1,482)||TC ≥200 mg/dL||7.8||NR||NR||Kit et al.201518|
|LDL-C**||NHANES 1999-2004||US, adults, age ≥20 years (n=1,628)||LDL-C||25.3||29.9||21.1||Hyre et al. 20075|
|NHANES 2009-2012||US, adolescents age 12-19 years||LDL-C||NR||7.1||7.4||Mozaffarian et al. 20156|
|HDL-C||NHANES 2011-2012||US, adults, age ≥20 years, (n=3,469)||HDL-C ≤40 mg/dL||17.0||26.4||9.0||Carroll et al. 201317|
|NHANES 2011-2012||US, children and adolescents age 8-17 years (n=1,482)||HDL-C ≤40 mg/dL||12.8||NR||NR||Kit et al. 201518|
Note: *, The American Heart Association defines Intermediate risk of hypercholesterolemia TC ≥200 mg/dL in adults, or >e;170 mg/dL in children and adolescents; high risk as TC ≥240 mg/dL in adults or ≥200 mg/dL in children and adolescents.19; ** High LDL-C levels warranting therapeutic lifestyle changes and consideration of lipid-lowering therapy are specified by the National Cholesterol Education Program Adult Treatment Panel–III guidelines as ≥100 mg/dL for patients with coronary heart disease (CHD) and/or CHD risk equivalent(s). For patients without CHD or risk equivalent, high LDL-C is defined as LDL-C levels ≥130 mg/dL for patients with two or more CHD risk factors and a 10-year CHD risk of 10-20%, ≥160 mg/dL for patients with two or more CHD risk factors and a 10-year CHD risk <10%, and ≥190 mg/dL for patients with 0-1 CHD risk factors. A person with high LDL-C is defined as having LDL-C levels stated above, or if taking cholesterol-lowering medication.5
Abbreviations: NR, not reported.
Hypercholesterolemia due to elevated TC levels does not increase linearly with age. In fact, NHANES 1999-2000 data showed a peak in TC levels between 55-64 years (37.4%) in females but in a younger age group (45-54 years) in males (22.9%).16
Hypertriglyceridemia affects approximately a third of the US adult population. However, the severe form (TG ≥500 mg/dL) is rare, affecting less than 2% of the US population.20,21 A breakdown of the TG levels in a 2001-2006 NHANES study of US adults (n=5,680, age ≥20 years) extrapolated that while 14.2% of the US population had borderline-high TG levels (150-200 mg/dL), 16.3% had high TG levels (200 to <500 mg/dL), 1.7% had severe levels (500-2,000 mg/dL), and 0.0004% had very severe TG levels (>2,000 mg/dL).22
Table 7: Prevalence of hypertriglyceridemia by sex in the United States.
|Data source||Population||Level of Hypertriglyceridemia||Prevalence (%)||Reference|
|NHANES 1994-2004||US adults, age ≥20 years n=5,610)||Hypertriglyceridemia (TG ≥150 mg/dL)||33.1||36.7||29.6||Ford et al. 200920|
|Hypertriglyceridemia (TG ≥200 mg/dL)||17.9||21.5||14.4|
|Severe hypertriglyceridemia (TG ≥500 mg/dL)||1.7||2.8||0.8|
|Very severe hypertriglyceridemia (TG ≥1000 mg/dL)||0.4||NR||NR|
|NHANES 1999-2006||US, adolescents, age 12-19 years (n=270)||Hypertriglyceridemia (TG ≥150 mg/dL)||10.2||11.4||8.8||Centers for Disease Control and Prevention. 201023|
|NHANES 2009-2012||US, adolescents, age 12-19 years||Hypertriglyceridemia (TG ≥150 mg/dL)||NR||10.0||6.5||Mozaffarian et al. 20156|
Abbreviations: TG, triglycerides; NR, not reported.
Elevated triglyceride levels in the US population increase with age to peak between 40-59 years of age, with little change thereafter (Table 8).
|Data source||Population||Age||Prevalence (%)|
|NHANES 2009-2012||US, adults, age ≥20 years (n=4,881)||20-39 years||19.9|
Source: Carroll et al. 20153
Several US studies examining lipid abnormalities by race/ethnicity and sex have reported elevated TC and depressed HDL-C level to be highest in Hispanic/Latinos and lowest in blacks (Table 9).17 In addition, elevated LDL-C is reported to be highest in whites and lowest in Mexican/Americans (Table 9).5
Table 9: Prevalence of hypercholesterolemia and hypertriglyceridemia in adults by race/ethnicity in the United States.
|Lipid disorder||Data source||Population||Category/Ethnicity||Prevalence (%)||Reference|
|Hypercholesterolemia||NHANES 2011-2012||US, adults, age ≥20 years (n=3,469)||TC ≥240 mg/dL||Carroll et al. 201317|
|NHANES 1994-2004||US, adults, age >e;20 years (n=1,628)||LDL-C ≥130 mg/dL||Hyre et al. 20075|
|NHANES 2011-2012||US, age ≥20 years (n=3,469)||HDL-C||Carroll et al. 201317|
|Hypertriglyceridemia||NHANES 1999-2004||US, adults, age ≥20 years (n=5,610)||TGs ≥150 mg/dL||Ford et al. 200920|
Abbreviations: TC, total cholesterol; LDL-C low-density lipoprotein cholesterol; NH, non-Hispanics.
Risk factors for hypercholesterolemia and hypertriglyceridemia have been declining in the last two to three decades in children, adolescents, and adults (Table 10). The favorable changes in lipid levels in the US over time are suggested to be due to a combination of factors, including healthier diet and lifestyles and increase in the use of statin monotherapy.3
Table 10: Declining trends in risk factors for hypercholesterolemia and hypertriglyceridemia in the United States.
|Lipid disorder||Data source||Population||Lipid Profile||Prevalence (%)||Reference|
|Hypercholesterolemia||NHANES 1976-1980 to 2007-2010||US, adults, age ≥20 years (n=7,044)||1976-1980||2007-2010||Kuklina et al. 200921|
|NHANES 1999-2000 to 2011-2012||US, children and adolescents, age 8-17 years (n=1,482)||1999-2000||2011-2012||Kit et al. 201518|
|TC (≥200 mg/dL)||10.6||7.8|
|HDL-C (≤40 mg/dL)||17.9||12.8|
|non-HDL-C (≥145 mg/dL)||13.6||8.4|
|Hypertriglyceridemia||NHANES 2001-2004 to 2009-2012||US, adults, age ≥20 years (n=4,115 for 2001-2004; n=4,881 for 2009-2012)||2001-2004||2009-2012||Carroll et al. 20153|
|TG (≥150 mg/dL)||33||25|
Note: *, High LDL-C ≥100 mg/dL for patients with coronary heart disease (CHD) and/or CHD risk equivalent(s), ≥130 mg/dL for patients with two or more CHD risk factors and a 10-year CHD risk of 10-20%, ≥160 mg/dL for patients with two or more CHD risk factors and a 10-year CHD risk <10%, and ≥190 mg/dL for patients with 0-1 CHD risk factors. A person with high LDL-C is defined as having LDL-C levels stated above or if taking cholesterol-lowering medication.5
Geographical differences in the prevalence of hypercholesterolemia have also been reported in the US. A 2009 household survey of 9,612 adults (age ≥20 years) in a rural region in Upstate New York, (adjusted for age, sex, and education) found male farmers had significantly lower prevalence of hypercholesterolemia (odds ratio, OR, 0.7) than rural non-farm residents, but not lower prevalence of heart disease or stroke. Although the farmers had worse health behaviors such as screening, vaccinations, regular health care provider; the lower hypercholesterolemia rates were presumably due to lower rates of smoking (OR 0.6) and higher physical labor (OR 2.61).24
According to the Centers for Disease Control and Prevention (CDC), the death rate in the US from CVDs declined by 29% from 1999 (30.3%) to 2013 (23.5%); however, CVDs remain the number one cause of mortality in the US, accounting for 611,105 of the 2,596,993 all-cause deaths in 2013.25 The declining death rate reflects favorable changes in the lipid levels in the US (as shown in Demographic Differences section above). Data from NHANES 1988-1994 (n=16,573) and 2007-2010 (n=11,766), in US adults, showed favorable decreases, over the 22-year time period, in serum levels of TC (206 to 196 mg/dL), LDL-C (129 to 116 mg/dL), non-HDL-C (155 to 144 mg/dL) and TGs (118 to 100 mg/dL), as well as favorable increases in HDL-C (50.7 to 52.5 mg/dL) and the use of lipid lowering medication (3.4% to 15.5%).26
Based on analysis of data collected in the crosssectional NHANES 1996 to 2006, the prevalence of hypercholesterolemia in US adults remained stationary from 1999 (53.2%) to 2006 (56.1%) (Table 11).2 In addition, only 50% of patients at borderline high risk were aware of their elevated cholesterol levels, and the condition was controlled by medications in fewer than 20%.
Table 11: Prevalence of checks, awareness, treatment, and control of hypercholesterolemia in the United States.
|Data source||Population||Hypercholesterolemia||Prevalence (%)|
|NHANES 1999 to 2006||US, adults age ≥20 years, unadjusted (n=18,053)||TC ≥200 mg/dL||1999||2006|
|Awareness of condition||42.0||50.4|
|TC ≥240 mg/dL||1990||2006|
|Awareness of condition||65.4||74.6|
|HDL-C (≤40 mg/dL)||17.9||12.8|
Source: Ford et al. 20102
Analysis of NHANES data from 1999 to 2004 showed a gradual increase in the use of cholesterol-lowering medication and in improvements in controlling hypercholesterolemia to the target lipid levels with medication (Table 12).
Table 12: Lipid-lowering treatments for hypercholesterolemia in the United States.
|Data source||Population||Treatment||Prevalence (%)|
|NHANES 1999-2000||US, adults, age ≥20 years (n=1,770)||Statin use (LDL-C in statin users: 119 mg/dL)||19.6|
|Control target of LDL-C achieved*||49.7|
|NHANES 2001-2002||US, adults, age ≥20 years (n=2,094)||Statin use (LDL-C in statin users: 112 mg/dL)||27.3|
|Control target of LDL-C achieved*||67.4|
|NHANES 2003-2004||US, adults, age ≥20 years (n=1,911)||Statin use (LDL-C in statin users: 100.7 mg/dL)||35.9|
|Control target of LDL-C achieved*||77.6|
Source: Mann et al. 200827
Note: *, National Cholesterol Education Program Adult Treatment Panel –III guidelines for LDL-C control recommend the following targets: <100 mg/dL, years, respectively.5
A decrease in the prevalence of CVDs in the last two decades is partially attributed to increased use of lipidlowering drugs. Key findings from NHANES 2003 to 2012 in adults age >40 years showed a steady increasing trend from 20% to 28% in the use of cholesterol lowering drugs, and from 18% to 26% in the use of statins. In subjects with hypercholesterolemia, 54% were taking cholesterollowering medications in 2012.28
Although statins lower vascular morbidity and mortality in patients with hyperlipidemia, 10-15% of patients reported experiencing increased incidence of myalgia.29 In fact, statin intolerance was reported in 5-20% of patients, and discontinuation of treatment was common, especially in patients on high-intensity statins.29 Alternative therapies under investigation include PCSK9 inhibitors, which prevent the binding of PCSK9 to the LDL receptor. PCSK9 inhibitors appear to have milder side-effects than statins, although further data on safety, morbidity, and mortality are still pending from long-term clinical trials.29 Importantly, the FDA recently approved the use of PCSK9 inhibitors alirocumab and evolocumab in July and August 2015 respectively. While hypertriglyceridemia (TG ≥150 mg/dL) is common in the US population, the use of available prescription medications is low, as highlighted by a 5-year crosssectional study (Table 13).
Table 13: Percentage of hypertriglyceridemia patients receiving treatment in the United States.
|Data source||Population||Triglyceride Levels||Prevalence (%)||Percentage of patients using 1 of 3 hypertriglyceridemia treatments (fenofibrate, gemfibrozil, or niacin)|
|NHANES 1999-2004||US adults, age ≥20 years (n=5,610)||≥150 mg/dL||33.1||2.6|
Source: Ford et al. 200920
Therapeutic options in patients with mild-moderate hypertriglyceridemia (TG 150-500 mg/dL) include the use of statins to reduce levels of LDL-C and TGs, and the risk of CVDs. A recent retrospective cohort analysis also suggested decreased incidence of pancreatitis in association with statin use30,but these patients are generally not at high risk of pancreatitis, unlike those with severe hypertriglyceridemia (>500 mg/dL), who may additionally require treatment with long-chain omega-3 fatty acids, fibrates or niacin.31 Currently available therapies for hypertriglyceridemia are highlighted in Table 14.
Table 14: Health outcomes of lipid-lowering therapies for treatment of hypertriglyceridemia in the United States.
|Randomized, doubleblinded, crossover design, hospital||US, adults age 19-59 years, Moderately hypertriglyceridemic and modestly hypercholesterolemic, normal LDL (n=11; 8 male, 3 female)||Fenofibrate||TG reduced by 45%, TC reduced by 14%, no changes in HDL or LDL||Capell et al. 200332|
|Multinational, double-blind, randomized, out-patient study-EVOLVE trial 2011-2012||US adults, age ≥18 years, 3:1 ratio male:female, severe hypertriglyceridemia, TG ≥500-Omega-3 carboxylic acids (OM3-CA)TG reduced by 25.5-30.9%Kastelein et al. 201433|
|Retrospective cohort study 2006-2012, integrated healthcare system||US, adults, age ≥18 years, TG 200-500 mg/dL (n=707,236)||Simvastatin or atorvastatin||Statins reduced the risk of acute pancreatitis: incidence rate ratio RR= 0.6 or when adjusted RR=0.29||Wu et al. 201530|
|Randomized, controlled, double-blind 6-week trial||US, mean age 60.8 years, 95.3% used a statin, TG≥200 mg/dL (n=647)||Omega-3 carboxylic acids (OM3-CA)||TG reduced by 14.6-20.6%||Dunbar et al. 201534|
|Placebo-controlled study||US, severe hypertriglyceridemia, TG>e;00 mg/dL||Omega-3 carboxylic acids (OM3-CA)||TG reduced by 25-30%||Zhao et al. 201535|