Prevalence

Elevated cholesterol is a well-established and modifiable risk factor for cardiovascular disease (CVD). In 2008 there were an estimated 17.3 million CVD deaths worldwide, 2.6 million (15%) of which were caused by hyperlipidemia. Data from the 2012 National Health and Nutrition Examination Survey (NHANES) indicated that nearly 31 million (13%) adults in the United States over the age of 20 years have a total cholesterol 240 mg/dL or higher and about 74 million (32%) have a low-density lipoprotein cholesterol (LDL-C) 130 mg/dL or higher and/or are taking a cholesterol lowering medication. This prevalence increases with aging.

Globally, the average prevalence of hyperlipidemia, defined as a total cholesterol 240 mg/dL or higher, is estimated at 39%. The global prevalence of hyperlipidemia is strongly related to socioeconomic factors, with total cholesterol levels in high income countries more than twice the levels observed in lower income countries. The highest clustering of hyperlipidemia around the world is observed in European countries with a prevalence of 54%, whereas African countries have the lowest prevalence at 23%. However, rapidly developing areas such as Southeast Asia and the Pacific region have demonstrated a mean increase in total cholesterol of approximately 3 mg/dL per decade between 1980 and 2008.

Awareness, Treatment, and Temporal Trends

Despite widespread screening, a quarter of individuals with a high LDL-C were unaware of their diagnosis between 1999 and 2006. Statin therapy is the primary medication prescribed to treat hyperlipidemia, accounting for more than 90% of prescriptions; from 2003 to 2012 and during this time the percent of U.S. adults over 40 years of age prescribed statin therapy increased from 16% to 23%. Furthermore, as a result of the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol treatment guidelines, which base the decision to treat hyperlipidemia on cardiovascular risk rather than LDL-C level, the total number of U.S. adults meeting eligibility criteria for statin therapy is as high as 50%. These new guidelines have an even greater impact among individuals over the age of 60 years, in whom nearly 80% would be identified to benefit from statin therapy after a clinician-patient risk discussion.

Statin therapy was approved by the United States Food and Drug Administration (FDA) in 1987 and contributed to a significant reduction in both total cholesterol (mean level from 206 to 196 mg/dL) and LDL-C (mean 129 to 116 mg/dL) among U.S. adults between 1988 and 2010. In high income countries a temporal decline in total cholesterol similar to that in the U.S. has also been observed. This inverse relationship between temporal reductions in total cholesterol and per capita income, particularly among patients with prevalent vascular disease or who are at high CVD risk, is partly attributable to the higher use of cholesterol lowering medications in affluent countries. Therefore, we are likely to see a continued decline in cholesterol levels among developed nations with higher per capita income as a result of an increase in cholesterol lowering medication use.

Cardiovascular Risk Factor Clustering: the Dyslipidemia and Hypertension Overlap

Among U.S. adults 50 years of age or older, less than one-third have ideal blood pressure, total cholesterol, or body mass index (BMI) and only 35% have ideal fasting blood glucose. Accordingly, CVD risk factors more often occur together rather than in isolation and between 1991 and 1999, U.S. adults with hypertension had an increase in the prevalence of at least one additional CVD risk factor from 66% to 73%. Similarly, more than half of hypertensive U.S. adults who do not have CVD are estimated to have one or more of the following: hyperlipidemia, diabetes, or increased BMI.

High blood pressure and dyslipidemia are also closely interrelated with metabolic syndrome and in 2009 to 2010 approximately one-quarter of U.S. adults had metabolic syndrome. Adults with high blood pressure (systolic blood pressure [SBP] ≥130 and/or diastolic blood pressure [DBP] ≥ 80 mm Hg), low HDL-C (<40 mg/dL), and hypertriglyceridemia (≥150 mg/dL) meet the criteria for metabolic syndrome regardless of their other cardiovascular risk factors based on the National Heart Lung and Blood Institute (NHLBI)/AHA definition. Among individuals with metabolic syndrome, 49% had high blood pressure, 85% had hypertriglyceridemia, and 60% had low HDL-C.

It is no surprise, then, that between one-third to two-thirds of all U.S. adults with hypertension also have hyperlipidemia and that this coprevalence has remained unchanged over the last 20 years. Among 57,573 hypertensive primary prevention patients from the Kaiser Permanente Northwest health maintenance group, 24% had concurrent hyperlipidemia ( Fig. 38.1 ). Similarly, in a study of 371,221 U.S. Veterans with a mean age of 58 years between 1998 and 2001, 52% had hypertension, 36% had dyslipidemia, and 31% had both hypertension and dyslipidemia. There has been a significant decline in lipid levels from the early 1990s to the late 2000s and among individuals with combined hypertension and hyperlipidemia the mean total cholesterol decreased from 235 to 202 mg/dL and the mean LDL-C decreased from 154 to 120 mg/dL. However, less than one-third of individuals were treated to their goal blood pressure and cholesterol goal.

Overlap between hypertension, dyslipidemia and diabetes in a contemporary managed care population.

(From Selby JV, Peng T, Karter AJ, et al. High rates of co-occurrence of hypertension, elevated low-density lipoprotein cholesterol, and diabetes mellitus in a large managed care population. Am J Manag Care. 2004;10[Part 2]:163-170.)

Risk Assessment

The 2013 guidelines introduced the calculation of a patient’s 10-year ASCVD risk estimate based on the Pooled Cohort Risk Assessment Equations as the primary determinant to identify eligibility for lipid lowering therapy for primary prevention. However, validation analyses in modern U.S. cohorts have suggested significant overestimation of risk using the Pooled Cohort risk equation, especially for individuals in whom the estimated risk was relatively high. Nevertheless, analyses from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (baseline 2003 to 2007) and from the Copenhagen General Population Study (baseline 2003 to 2008) have suggested that the ASCVD equation performs better than other statin allocation approaches.

The 7.5% cutoff for the Pooled Cohort equation dramatically increased the number of individuals who are eligible for statin therapy because it is more sensitive, but less specific than prior guideline recommendations. Accordingly, approximately one-third of all U.S. adults are now eligible for statin therapy and among these individuals, approximately two-thirds have prevalent hypertension. In the context of concerns regarding overestimation, additional risk stratification information, such as a premature family history of ASCVD, a coronary artery calcium (CAC) score of more than 300 Agatston units or higher than 75th percentile for age/gender, or an elevated lifetime risk of ASCVD, are recommended by ACC/AHA as ‘tie-breaker’ tests for intermediate risk patients. It may also be most reasonable to consider the use of these additional risk stratification tools (particularly CAC) in selected patients with an estimated risk that is higher than 7.5%, based on clinical judgment. Furthermore, the patient-physician risk/benefit discussion is essential before the initiation of statin therapy regardless of a patient’s absolute risk.

Loss of Low-Density Lipoprotein Cholesterol Treatment Goals and Recommended Pharmacologic Therapy

The most controversial aspect of the 2013 lipid guidelines was the abandonment of LDL-C treatment goals. This was largely attributed to a report from the Institute of Medicine on guideline development and subsequent NHLBI Advisory Council recommendation to base guidelines on the highest-quality evidence available, specifically, randomized controlled trials. Lipid lowering trials have evaluated the effect of statin therapy according to specific doses and there has not been a major lipid treatment trial with the primary outcome of evaluating treatment to a specific LDL-C goal.

Patients are now recommended for treatment with either moderate or high intensity statin therapy based on their estimated risk from the Pooled Cohort equation. High intensity statins are defined as those that lower LDL-C by 50% or more whereas moderate intensity statins are those that lower LDL-C by 30% to 50%. High intensity statin therapy is recommended for those 75 years of age or older with prevalent ASCVD, those with a LDL-C 190 mg/dL or higher, and patients with diabetes who have an estimated risk 7.5% or higher 10-year risk. Nondiabetic patients with a 7.5% or higher 10-year risk can be treated with either moderate or high intensity statin therapy. All other patients meeting statin therapy criteria are recommended to be treated with a moderate intensity statin. Low intensity statin therapy is recommended only in patients unable to tolerate moderate or high intensity statin therapy.

Despite the abandonment of LDL-C treatment goals in the ACC/AHA recommendations observational data show a consistent inverse and linear relationship between total cholesterol and CHD without an obvious lower limit of total cholesterol. This relationship was also observed in an individual level meta-analysis examining the observed reductions in LDL-C among 38,153 participants enrolled in randomized controlled statin treatment trials. Participants with an achieved LDL-C less than 50 mg/dL had a 19% reduction in major CVD compared with those with an achieved LDL-C of 75 to 100 mg/dL. Therefore, the majority of available evidence, inclusive of mechanistic and observational data, demonstrates that even lower LDL-C levels with proven therapy are associated with a further reduction in CVD.

Although LDL-C is expected to be reduced by 30% to 50% for moderate intensity and more than 50% for high intensity statin therapy, there is significant heterogeneity in the percent LDL-C reduction between individuals. Accordingly, the 2013 Guidelines recommend to monitor a patient’s individual response to statin therapy 4 to 12 weeks after statin initiation or dose adjustment and annually thereafter. Patient demographics, cigarette smoking, diet, exercise, triglyceride levels, and physical activity can contribute to differing percent LDL-C lowering between patients. However, nonadherence to statin therapy is the most frequent contributor to achieving less than anticipated reductions in LDL-C.

Interaction of Hypertension and Dyslipidemia in Estimating Atherosclerotic Cardiovascular Disease Risk

Four of the nine variables used in the Pooled Cohort equation to calculate estimated 10-year ASCVD risk incorporate blood pressure and cholesterol: (1) SBP, (2) treatment for hypertension, (3) total cholesterol, and (4) HDL-C. Observational research suggests a significant interaction between blood pressure and cholesterol on future events, although there is no formal interaction term in the ASCVD equation. Nonetheless, SBP has the largest coefficient of any variable in the ASCVD equation for African-American women and the second largest coefficient after age for African-American men. Moreover, SBP has a larger coefficient than diabetes in all gender/race versions of the equation.

In a study of U.S. Veterans, patients with combined hypertension and hyperlipidemia had a two-fold to three-fold greater prevalence of ASCVD and a three-fold to four-fold greater prevalence of myocardial infarction compared with Veterans with either hypertension or dyslipidemia alone. The Multiple Risk Factor Intervention Trial (MRFIT), which included 361,662 men with an average age of 46 years, showed similar results with follow-up through 1986. Participants in the lowest quintile of both SBP and total cholesterol had the lowest risk of CHD, whereas participants in the highest quintiles of SBP and total cholesterol had an approximately ten-fold increased CHD risk.

It is important to recognize the significant increase in CVD risk for patients with both hypertension and hyperlipidemia compared with patients with these risk factors in isolation. Effort should be made to ensure they are controlled in tandem to adequately reduce CVD risk. Therefore, the absence of hyperlipidemia does not equate with an absence of benefit for lipid lowering in hypertensive patients at high risk for ASCVD.

A Comprehensive Treatment Approach

A comprehensive treatment approach is required as lipid abnormalities among hypertensive adults are closely linked with other CVD risk factors. Relying solely on the pharmacologic reduction of lipid levels represents a missed opportunity to address the underlying problems leading to a poor CVD risk factor profile. A comprehensive approach can target common modifiable factors that drive both elevated cholesterol and blood pressure levels such as unhealthy diet, low activity level, and adiposity. In addition, pharmacologic therapy should only be implemented if lifestyle modification provides inadequate results.

To this end, we recommend the simple “ABCDEF” approach ( Table 38.1 ). The ABCDEF approach is easy to use and recall by health care providers and patients, feasible in the context of clinic time constraints, and employs evidence-based recommendations. Furthermore, it is a simple tool that can translate complex and lengthy CVD prevention guidelines into a comprehensive and straightforward heuristic.

It is well established that a healthy diet (one of the ‘D’ components of the ABCDEF tool) can improve both blood pressure and lipid parameters. This was highlighted in the Prevención con Dieta Mediterránea (PREDIMED) study that reported a 30% reduction in myocardial infarction, stroke, or death from CVD causes among 7447 Europeans randomized to a Mediterranean diet enriched with olive oil (crude event rate 8.1 per 1000 person years, hazard ratio [HR] 0.70 [95% confidence interval {CI} 0.54 to 0.92]) or nuts (crude event rate 8.0 per 1000 person years, HR 0.72 [95% CI, 0.54 to 0.96]), with point estimates driven by reduced stroke, both compared with a control diet (11.2 per 1000 person years).

A subsequent nested case-control analysis from PREDIMED demonstrated a reduction in 24 hour ambulatory blood pressure of −2.3 mm Hg (95% CI, −4.0 to −0.5) for the olive oil enriched diet and −2.6 mm Hg (95% CI, −4.3 to −0.9) for the nut enriched diet at 1 year of follow-up. Similarly, there was a reduction of changes in total cholesterol from baseline to 1 year of −11.3 mg/dL for the olive oil enriched diet and −13.6 mg/dL for the nut enriched diet.

Other diets have also been shown to reduce both blood pressure (BP) and cholesterol and therefore it is more important for patients to adhere to the overall features of a heart-healthy diet endorsed by 2013 ACC/AHA lifestyle guidelines rather than to any one rigid diet. These guidelines recommend increased intake of vegetables, fruits, and whole grains and a reduced intake of sweets, sugar-sweetened beverages, and red meat. Moderate intake of low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts is also recommended. This pattern can be achieved by following plans such as the PREDIMED Mediterranean diet, DASH (dietary approaches to stop hypertension) dietary pattern, the United Department of Agriculture (USDA) food pattern, or the AHA diet. For hypertensive individuals, dietary sodium should be less than 2400 mg, and preferably closer to 1500 mg, per day. However, in the case of hypertensive individuals who have elevated cholesterol, further attention should be directed to lowering percent of calories from saturated fat (to 5% to 6% of total) and limiting trans fats.

In a meta-analysis of randomized controlled trials evaluating the impact of exercise (the ‘E’ component of the ABCDE tool) on blood pressure control and other CVD risk factors there was an average reduction in blood pressure of −7/−5 mm Hg after exercise interventions. Consistent with findings from other groups there was also a reduction in triglycerides and an increase in high density lipoprotein-cholesterol (HDL-C), with nonsignificant reductions in LDL-C and total cholesterol. Mora et al reported that the 27% of the reduction in CVD outcomes as a result of exercise was accounted for by improvements in blood pressure and 19% by improvements in lipids.

Finally, the effect of weight loss on lipid and blood pressure control among hypertensive adults must be considered (diet and weight management is one of the ‘D’ components of the ABCDEF approach). Addressing diet and exercise will help most adults lose weight. However, studies assessing the durability of these interventions on sustained weight loss and long-term CVD outcomes have been mostly disappointing. Although new mobile health technologies have the potential to help sustain healthy lifestyle behaviors and weight loss, few data exist on the impact of these modalities on long-term lipid and blood pressure control. However, bariatric surgery has proven highly effective, particularly among patients with diabetes. In the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial, which randomized 150 diabetics to one of three intervention groups (medical therapy, gastric bypass, or sleeve gastrectomy) patients with weight-loss surgery had improvements in HgbA1C, BMI, triglycerides, HDL-C, and proteinuria after 3 years of follow-up. Although LDL-C and blood pressure did not differ significantly between the groups, this was attributed to differential medication use in the study arms over follow-up.

Evidence for Combination Treatment of Hypertension and Dyslipidemia

Although the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack-Lipid-Lowering Trial (ALLHAT-LLT) did not demonstrate a reduction in mortality or CHD events among 10,355 hypertensive adults with a mean baseline LDL-C of 146 mg/dL randomized to pravastatin, there was substantial crossover to statins in the control group. In contrast, the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) trial did report a reduction in nonfatal myocardial infarction, fatal CHD, and stroke over 3.3 years of follow-up for atorvastatin therapy among 19,342 hypertensive adults with a mean baseline LDL-C of 131 mg/dL. Mean BP control did not differ in either the statin or control arm of both of these trials as a result of factorial randomization. However, the relative reduction in total cholesterol of 24% in ASCOT-LLA was far higher than seen in the ALLHAT-LLT study (9.6%). Although mortality was not reduced at 3.3 years, long-term follow-up of ASCOT-LLA out to 11 years did demonstrate a significant reduction in death, despite substantial crossover to statin therapy in the control arm after trial completion.

The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which randomized 17,802 adults (57% had a diagnosis of hypertension) with an LDL-C less than 130 mg/dL and a high-sensitivity C-reactive protein 2 or more mg/L to rosuvastatin versus placebo also reported significant benefit for lower LDL-C. Given the median SBP at the baseline visit of JUPITER was 134 mm Hg, the majority of the JUPITER population may benefit from the consideration of additional antihypertensive therapy based on results from the Systolic BP Intervention Trial (SPRINT) that showed a reduction in all-cause mortality in the group treated to a goal SBP less than 120 mm Hg.

Additional evidence for aggressively reducing LDL-C in high risk hypertensive adults comes from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) in which 18,144 adults who were hospitalized with acute coronary syndrome with a LDL-C less than 125 mg/dL at baseline were randomized to simvastatin 40 mg (achieved LDL-C of 70 mg/dL) versus simvastatin 40 mg plus ezetimibe 10 mg (achieved LDL-C of 54 mg/dL). Over 60% of patients enrolled in this trial had hypertension and there was a 6% reduction in the primary endpoint of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke ( p = 0.016) over 7 years of follow-up. Therefore, using proven therapy, there is a linear relationship between ASCVD and the reduction of LDL-C among a wide range of hypertensive patients with a history of, or at risk for, CVD.

The Polypill

Some experts have advocated for the use of combination therapy for hyperlipidemia and hypertension in persons at elevated CVD risk: the concept of a “Polypill.” The motivation for a Polypill, also termed a fixed-dose combination (FDC), is to improve adherence, lower cost (particularly attractive in low-income countries where personalized medicine is more challenging as a result of limited resources), and to increase the use of preventive therapies among suitable primary prevention populations. Adherence is particularly important for hypertensive adults with elevated cholesterol because as few as one in three adults remains adherent with both hyperlipidemia and hypertension cotherapy. Meta-analyses have demonstrated that, compared with placebo, FDCs resulted in meaningful reductions in SBP and DBP, and in total cholesterol and LDL-C, but that these reductions were less than what would have been expected from the component medications, based on trials of these agents taken as single medications. However, it is likely that, outside of trial settings (i.e., in the real world), the Polypill would likely perform as well, if not better, than the component medications by improving adherence.

In keeping with this, the Use of a Multidrug Pill in Reducing Cardiovascular Events (UMPIRE) trial, a pragmatic study in which the control patients were not given any support with their usual care medications, reported that subjects allocated to the FDC treatment arm had improved adherence and modest reductions in SBP (2.6 mm Hg, p < 0.001) and LDL-C (4.2 mg/dL, p < 0.001) after a median follow-up of 15 months. Despite these encouraging results, in the absence of evidence for reduced hard CVD outcomes, which is currently being tested in a number of outcomes trials (TIPS3 and HOPE4), it is unlikely that the Polypill will be recommended for widespread use in the near future by guideline committees.

Modifying Effects of Statins on Blood Pressure and Antihypertensive Medications on Lipid Levels

Although observational data and mechanistic trials suggest that statins may independently lower blood pressure, posthoc exploratory blood pressure data from large outcomes trials suggest that the independent effects of statins on blood pressure lowering are likely small. Nonetheless, even a 2 mm Hg reduction in blood pressure at the population level could meaningfully reduce CVD.

Moreover, a number of antihypertensive medications can also alter lipid levels. Thiazide diuretics can mildly increase total cholesterol levels and beta-blockers can increase triglycerides and lower HDL-C. In contrast, alpha-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor-blockers may have mild beneficial effects on lipids. However, these lipid changes are typically mild and tend to normalize within the first year of therapy.

Emerging Therapies for Hyperlipidemia and Their Relationship With Blood Pressure Control

The addition of adjunctive nonstatin lipid lowering therapies to maximally tolerated statin therapy has had mixed results. However, more recent developments have generated great enthusiasm, particularly with the approval of Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which decrease LDL-C receptor degradation and increase recirculation of the receptor to the hepatocytes cell surface, thereby lowering of serum LDL cholesterol. The classes of new lipid medication that are furthest along in development include the PCSK9 inhibitors, the cholesteryl ester transfer protein (CETP) inhibitors, mipomersen (an antisense oligonucleotide that inhibits production of apolipoprotein B-100) and loperamide (a microsomal triglyceride transfer protein inhibitor). The latter two agents are expensive (current cost estimates are typically over $200,000 per year), associated with liver toxicities, and are only approved for use in patients with homozygous familial hypercholesterolemia and their discussion is beyond the scope of this chapter.

Although enthusiasm for the CETP inhibitors is currently waning, they are nonetheless pertinent to our discussion given their known off-target effects on blood pressure control. These agents are potent increasers of HDL-C and facilitate the exchange of cholesterol esters between HDL-C particles and apolipoprotein B-containing lipoproteins. However, despite reducing LDL-C by 25% and increasing HDL-C by 72%, torcetrapib, the first agent tested, increased mortality and CVD. The excess in events has been attributed to increases in aldosterone, cortisol, endothelin-1, which resulted in an increase in SBP of about 5 mm Hg. The next CETP agent tested, dalcetrapib, increased HDL-C by about 30%. Despite this, the DAL-OUTCOMES trial was stopped for futility and of note, SBP was increased by 0.6 mm Hg relative to placebo ( p < 0.001). Similarly, a large outcomes trial of evacetrapib was recently discontinued for futility. Only anacetrapib and TA-8995 remain under testing in large trials.

In contrast, the PCSK9 inhibitor class of agents has demonstrated dramatic LDL-C reductions as well as a signal for clinical benefit. Alirocumab and evolocumab were recently approved for use in familial hypercholesterolemia and in persons with clinical ASCVD who would benefit from additional LDL-C lowering on top of maximally tolerated statin therapy. Thus, these agents are now available for use in a wide range of high CVD risk hypertensive patients.

Both agents are given by subcutaneous injection and can cause large reductions in LDL-C levels (39% to 62% reduction for alirocumab and 47% to 56% for evolocumab) ( Table 38.2 ). Although results from definitive outcomes trials are still awaited, preliminary results point to a strong likelihood that this LDL-C reduction will translate into reduced CVD events in patients receiving these agents. The data that have been reported on the effects of PCSK9 on blood pressure suggest that both genetic and pharmacologic inhibition of the PCSK9 pathway has no adverse impact on hypertension control.

TABLE 38.2

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