Curr Hypertens Rep (2016) 18:76
DOI 10.1007/s11906-016-0683-0
HYPERTENSION AND OBESITY (E REISIN, SECTION EDITOR)
Management of Dyslipidemia in Patients with Hypertension,
Diabetes, and Metabolic Syndrome
Sundararajan Srikanth 1,2 & Prakash Deedwania 3
# Springer Science+Business Media New York 2016
Abstract
Purpose of Review The purpose of this review is to discuss
dyslipidemia in the various common clinical conditions in-
cluding hypertension, diabetes mellitus, and metabolic syn-
drome and review the current therapeutic strategy in these
settings.
Recent Findings Dyslipidemias are common in patients with
hypertension, diabetes mellitus, and metabolic syndrome.
Epidemiologic studies have shown a strong correlation be-
tween serum lipid levels and risk of atherosclerotic cardiovas-
cular disease. Multifactorial intervention strategies aimed at
controlling lipids, blood pressure, and blood glucose simulta-
neously achieve maximal reductions in cardiovascular risk.
Summary Dyslipidemia and metabolic abnormalities are
strongly associated with atherosclerosis and worse cardiovas-
cular outcomes. While pharmacotherapy with statins has been
proven to be beneficial for dyslipidemia, lifestyle modification
emphasizing weight loss and regular exercise is an essential
component of the interventional strategy. The common thread
underlying atherosclerosis and metabolic abnormalities is en-
dothelial dysfunction. Improved understanding of the role of
endothelium in health and disease can potentially lead to novel
therapies that may preempt development of atherosclerosis
and its complications.
This article is part of the Topical Collection on Hypertension and Obesity
* Prakash Deedwania
deed@fresno.ucsf.edu
1
UCSF School of Medicine, Fresno, CA, USA
2
Division of Cardiovascular Diseases, UCSF Program at Fresno CA,
Fresno, CA, USA
3
UCSF School of Medicine, San Francisco Suite 460, 2335 E Kashian
Lane, Fresno, CA 93701, USA
Keywords Dyslipidemia . Diabetes mellitus . Hypertension .
Metabolic syndrome . Atherosclerosis
Introduction
Endothelial dysfunction may be the initiating factor in the
development of vascular inflammation and atherosclerosis.
This dysfunction is characterized by impaired vascular perme-
ability, leucocyte–endothelial interaction, and platelet aggre-
gation. Dyslipidemia, hypertension, and insulin resistance
contribute to endothelial dysfunction and vascular inflamma-
tion leading to atherosclerosis. Atherosclerosis is a lipid-
driven inflammatory disorder of the arterial wall and elevated
level of circulating cholesterol carried by circulating apolipo-
protein B-containing lipoproteins is thought to be the major
cause.
Dyslipidemia and Atheroslcerosis
Atherogenic lipids have the ability to infiltrate the arterial wall
thereby initiating atherosclerosis. HDL, LDL, intermediate-
density lipoprotein (IDL), very low-density lipoprotein
(VLDL), and chylomicrons are the five major classes of lipo-
proteins. Of these, LDL is the predominant cholesterol-
carrying lipoprotein comprising approximately 75 % of cho-
lesterol carried by non-HDL particles, with the remaining
25 % of non-HDL-C in triglyceride-rich particles, which in-
clude VLDL, IDL, chylomicrons, and their remnants. Non-
HDL-C (calculated as total-C–HDL-C) represents the sum
total of cholesterol carried by all potentially atherogenic, apo
B-containing lipoprotein particles, including LDL, IDL, Lp
(a), VLDL (including VLDL remnants), and chylomicron par-
ticles and remnants [1, 2]. In the setting of metabolic
76 Page 2 of 10
syndrome and type 2 diabetes, atherogenic dyslipidemia man-
ifests in routine lipoprotein analysis by raised triglycerides and
low concentrations of HDL cholesterol [3•]. A more detailed
analysis usually reveals other lipoprotein abnormalities, e.g.,
increased remnant lipoproteins, elevated apolipoprotein B,
small LDL particles, and small HDL particles. All of these
abnormalities have been implicated as being independently
atherogenic.
After entering the arterial wall, the particles bind to extra-
cellular matrix molecules, and are modified through oxidation
and other processes, which increase their inflammatory prop-
erties and their unregulated uptake by macrophages [4]. The
macrophages become engorged with lipid, and turn into foam
cells forming Bfatty streaks^; they magnify the inflammatory
response through release of interleukins. This leads to smooth
muscle proliferation in the media resulting in the development
of a fibrous cap or plaque [5]. As the plaques mature and
atherogenic particles continue to infiltrate, lipid-rich areas
form within the fibrous plaque. Inflammation triggers process-
es that weaken the fibrous cap and make the plaque suscepti-
ble to rupture [6]. Thus, dyslipidemia plays an important role
in the initiation of atherosclerosis, progression to a mature
plaque and eventually, plaque instability, and rupture.
Atherosclerotic plaque rupture is generally the proximate
cause of acute coronary syndromes.
Epidemiologic studies have demonstrated a strong relation-
ship between serum cholesterol levels and increased ASCVD
risk, and, conversely, low rates of ASCVD are associated with
low levels of cholesterol. Observational data from the UKPDS
showed that a 1 mmol/L increase in LDL-C was associated
with a 57 % increase in CVD endpoints. Clinical trials includ-
ing the Heart Protection Study and Collaborative Atorvastatin
Diabetes Study amply demonstrate that lowering of LDL-C
with drugs will reduce the risk of CV events [7]. The impor-
tance of LDL-C in ASCVD is also substantiated by hereditary
conditions such as familial hypercholesterolemia (FH). In this
autosomal co-dominant genetic disorder characterized by very
high levels of LDL-C (and LDL particles) and early ASCVD,
the removal of apo B-containing lipoproteins by lipoprotein
apheresis has been shown to markedly reduce arterial wall
inflammation [8]. The beneficial impact of lowering athero-
genic cholesterol levels for reducing ASCVD risk is also sup-
ported by genetic studies of individuals with PCSK9 muta-
tions and with polymorphisms in the Niemann-Pick C1-like 1
(NPC1L1) protein, both of which result in reduced levels of
LDL-C throughout life [9•, 10].
Management of Dyslipidemia
In individuals at risk of developing cardiovascular disease
which include those with diabetes mellitus, hypertension,
and metabolic syndrome it is essential to aggressively manage
Curr Hypertens Rep (2016) 18:76
all modifiable risk factors. Hence multifactorial risk factor
modification addressing hyperglycemia, hypertension, and
dyslipidemia is emphasized. Various pharmacological and
non-pharmacological therapeutic interventions to treat the
metabolic and cardiovascular abnormalities have evolved over
the last century. Therapies that have been proven to have long-
term therapeutic benefit have generally shown concurrent im-
provement in insulin sensitivity and endothelial dysfunction.
The therapeutic goals for management of cardiovascular risk
facts have been outlined by the ACC, AHA, and the
Endocrine Society (see Table 1). They include reduction of
abdominal obesity, regular physical activity, dietary modifica-
tion, and treatment of specific cardiovascular risk factors as
identified. In the following sections individual components of
the therapeutic strategy will be briefly reviewed with a special
focus on management of dyslipidemia.
Lifestyle Modification
Current evidence suggests that the first step in the manage-
ment of patients with dyslipidemia and metabolic syndrome
should be focused on weight loss and increased physical ac-
tivity. Lifestyle modifications including diet, weight loss, and
physical exercise reduce insulin resistance, obesity and im-
prove endothelial function. The benefit of weight manage-
ment in controlling the metabolic syndrome is highlighted
by the CARDIA study [11]. In this observational study of
more than 5000 young individuals for 15 years between the
ages of 18 and 30 years, increasing BMI was associated with
progression of components of metabolic syndrome as opposed
to those who maintained a stable BMI over the same period.
Obese individuals can lose up to 0.5 kg/week by restricting
calories to less than 500–1000 kcal below daily requirements
[12]. Combining calorie restriction with regular exercise can
lead to a weight loss of 5–10 % from baseline over a 6 month
period. A realistic goal for weight reduction is a target of 7–
10 % over a 6 to 12 month period. Such reductions in body
weight are associated with much greater loss of visceral adi-
posity (the central problem in cardio-metabolic syndrome).
This marginal weight loss results in improvement of many
of the metabolic abnormalities [13].
Diet Intervention
Several dietary approaches have been advocated for treatment
of the metabolic syndrome. The Dietary Guidelines for
Americans recommend a balance between energy intake and
expe nditu re to maintain a healthy body weight.
Recommended macronutrient ranges for adults are 45–65 %
of energy from carbohydrate, 10–35 % from protein, and 20–
35 % of energy from fat. Avoiding excessive sodium intake
and limiting consumption of saturated fats, trans fats, refined
grains and added sugars are emphasized. Consumption of
Curr Hypertens Rep (2016) 18:76 Page 3 of 10 76

Table 1 The therapeutic goals and clinical recommendation for management of metabolic syndrome

Target Recommendations Goal

Abdominal obesity
Physical inactivity
Atherogenic diets
Smoking
High LDL cholesterol
High triglycerides
Low HDL cholesterol
High blood pressure
Elevated glucose
Prothrombotic state
Diet control and increased physical activity 10% weight loss in the first year and
continued weight loss thereafter
Moderate-intensity aerobic activity 5 days/week; Resistance training 30-60 min of exercise daily
2 days/week
Total fats 25-35 % of total calories, saturated fats <7 % of calories Reduced intake of saturated fats, trans
fats and cholesterol
Complete cessation Complete cessation
Lifestyle changes. Initiate statin therapy for primary prevention if Medium intensity or high intensity
LDL >190. For LDL 70–189, initiate therapy if >7.5 % 10-year stain therapy dictated by risk
ASCVD risk
No defined therapies or goals No defined goals
Lifestyle changes Insufficient data
Lifestyle therapy and antihypertensive drugs BP <140/90 for age <60 year; BP
<150/90 for age > 60 year
Lifestlye therapy and hypoglycemic drugs Reduction and maintenance of fasting
glucose 80-130 mg/dL; A1c < 7%
Consider low-dose aspirin when risk of CV events is higher than risk Reduction of prothrombotic state
of GI bleed or stroke

fruits and vegetables; nuts, peas, and legumes; whole grains;
lean sources of protein; low-fat or fat-free dairy products;
seafood; and liquid vegetable oils are recommended [14].
The 2015 DGAC evaluated three dietary patterns, all of
which have been associated with health benefits. These are
the healthy US-style pattern, the healthy Mediterranean-style
pattern, and the healthy vegetarian pattern. These have similar
food-based characteristics to those defined by the 2013 AHA/
ACC Guideline on Lifestyle Management and, compared to
the average American diet, are higher in vegetables, fruits, and
whole grains; low- or non-fat dairy; seafood, legumes, and
nuts; moderate in alcohol (for adults); lower in red and proc-
essed meats; and low in sugar-sweetened foods/drinks and
refined grains [15]. The Mediterranean diet which is high in
fruits, vegetables, nuts, whole grains and olive oil results in
improved lipid profile and insulin resistance as compared to a
low-fat diet [16, 17]. Objective data on other weight reducing
diets such as high-protein low carbohydrate diet is limited.
Foods with low glycemic index may be beneficial.
Exercise
Current guidelines recommend practical, regular, and moder-
ate regimens for exercise. The standard exercise recommen-
dation is a daily minimum of 30 min of moderate-intensity
physical activity (e.g., brisk walking). The Diabetes
Prevention Project (DPP) study showed that multiple metabol-
ic risk factors can be controlled and type 2 diabetes prevented
or delayed by controlling weight with regular exercise. The
study enrolled 3234 normotensive subjects who were mostly
obese and randomized them to intensive lifestyle
modification, metformin, troglitazone, or placebo. The meta-
bolic syndrome (using ATP III criteria) was present in 53 % of
DPP participants at baseline. In the remaining subjects, both
intensive lifestyle intervention and metformin therapy reduced
the risk of developing the metabolic syndrome. The rate of
development of diabetes/metabolic syndrome was least in the
intensive lifestyle modification group which consisted of low
fat diet and 150 min of walking per week [18]. Exercise may
be beneficial beyond its effect on weight loss by more selec-
tively removing abdominal fat, at least in women [19].
Pharmacologic Options
At present pharmacologic approach to address dyslipidemia in
the setting of various metabolic conditions primarily com-
prises of statins. Other groups of medications which have been
developed to address various concurrent abnormalities such as
hyperglycemia, obesity, and hypertension are also important
components of the therapeutic regimen. No specific drug has
been developed that can reverse or block the fundamental
abnormality/abnormalities that lead to insulin resistance, en-
dothelial dysfunction, and vascular inflammation.
Anti-Lipemic Therapy
Reducing elevated levels of atherogenic cholesterol will lower
ASCVD risk in proportion to the extent that atherogenic cho-
lesterol is reduced. This benefit is presumed to result from
atherogenic cholesterol lowering through multiple modalities,
including lifestyle and drug therapies. Pharmacotherapy in the
76 Page 4 of 10
management of dyslipidemia has been enormously successful.
Multiple RCTs, involving, in aggregate, hundreds of thou-
sands of participants, have shown that drug therapies (partic-
ularly statins) that lower atherogenic cholesterol levels are
effective in reducing ASCVD morbidity and mortality [20,
21]. The Cholesterol Treatment Trialists’ meta-analysis of
more- vs less-intensive statin regimens demonstrated that a
1.0 mmol/L (38.7 mg/dL) change in LDL-C resulted in a
22 % relative risk reduction (hazard ratio of 0.78) for major
ASCVD events [20]. In addition, there was no evidence of an
LDL-C threshold within the range studied. Larger LDL-C
reductions, for example 2 to 3 mmol/L (77.4–116.1 mg/dL),
could yield up to 40 to 50 % relative risk reduction for
ASCVD. The ATP-III guidelines emphasized that LDL reduc-
tion is the primary target in lipid management even in the
metabolic syndrome with low HDL and triglycerides being
secondary targets [22].
In all adults (≥20 years of age), a fasting or non-fasting
lipoprotein profile should be obtained at least every 5 years.
At a minimum, this should include total cholesterol and HDL-
C, which allows calculation of non-HDL-C (total-C–HDL-C).
Lipoprotein lipid measurement and ASCVD risk assessment
should be repeated in 5 years, or sooner based on changes in
ASCVD risk factors (including weight gain), a premature
ASCVD event in a first-degree relative, evidence of
ASCVD in the patient, or a new potential secondary cause
of dyslipidemia. For those with atherogenic cholesterol in
the desirable range, public health recommendations regarding
lifestyle should be emphasized. When intervention beyond
public health recommendations for long-term ASCVD risk
reduction is used, levels of atherogenic cholesterol (non-
HDL-C and LDL-C) should be the primary targets for thera-
pies. Although LDL-C has traditionally been the primary tar-
get of therapy in previous lipid guidelines and in the practice
Table 2 Risk assessment
Very high risk
Known ASCVD
Diabetes mellitus with ≥2 other major ASCVD risk factors
or end-organ damage
High risk
Diabetes mellitus with 0–1 other major ASCVD risk factors
Chronic kidney disease stage 3B or 4
LDL-C ≥190 mg/dL
≥3 major ASCVD risk factors present
Moderate risk
2 Major ASCVD risk factors present (If quantitative risk score reaches
high-risk threshold or high risk is indicated by additional testing such
as coronary artery calcium score, high-sensivity CRP, strong family
history etc., assign to high-risk category)
Low risk
No or 1 risk factor and no other major indicators of higher risk
Curr Hypertens Rep (2016) 18:76
of clinical lipidology, the NLA Expert Panel’s consensus view
is that non-HDL-C is a better primary target for modification
than LDL-C. Non-HDL-C comprises the cholesterol carried
by all potentially atherogenic particles, including LDL, IDL,
VLDL, and VLDL remnants, chylomicron particles, and chy-
lomicron remnants, and Lp (a). Both non-HDL-C and LDL-C
are considered targets for lipid-altering therapy, and goals for
therapy have been defined for both. Using non-HDL-C as a
target for intervention also simplifies the management of pa-
tients with high triglycerides that is seen frequently in the
setting of metabolic syndrome (200–499 mg/dL).
In addition to lipoprotein lipid levels, ASCVD risk assess-
ment includes evaluation of other major ASCVD risk factors
and other conditions known to be associated with high or very
high risk for an ASCVD event (Table 2). Treatment with
statins is recommended based on 10-year risk of cardiovascu-
lar events (nonfatal MI, CHD death, or nonfatal and fatal
stroke) with goal of therapy being, reduction in LDL by half
from baseline if initiated. Risk assessment is made to deter-
mine the clinical risk category the individual falls under. Very
high-risk conditions include individuals with clinical
ASCVD, diabetes mellitus (type 1 or 2), with ≥2 major clinical
risk factors or evidence of end-organ damage (estimated glo-
merular filtration rate, 60 mL/min/1.73 m2). High-risk condi-
tions include severe hypercholesterolemia phenotype (LCL-
C ≥ 190 mg/dL), diabetes mellitus (type 1 or 2) with 0 or 1
major clinical risk factor and chronic kidney disease stage 3B
or 4 (estimated glomerular filtration rate <45 but >15 mL/kg/
1.73 m2). If above conditions do not exist, classification may
be done by counting major ASCVD risk factors; 0–1 risk
factor being low risk, 2 major ASCVD being moderate risk
and ≥3 major ASCVD risk factors being high risk.
Quantitative risk scoring may be considered for risk refine-
ment, particularly in patients with moderate risk. Three com-
monly used risk calculators are: ATP III Framingham risk
calculator, Pooled Cohort Equations (ACC/AHA) and
Framingham long-term risk calculator.
Table 3 Moderate- vs high-intensity statins
High-intensity statin Moderate-intensity statin
LDL-C reduction ≥50 % LDL-C reduction 30–50 %
Atorvastation, 40–80 mg Atorvastatin, 10–20 mg
Rosuvastatin, 20–40 mg Fluvastatin, 40 mg bid
Fluvastatin XL, 80 mg
Lovastatin, 40 mg
Pitavastatin, 2–4 mg
Pravastatin, 40–80 mg
Rosuvastatin, 5–10 mg
Simvastatin, 20–40 mg
Curr Hypertens Rep (2016) 18:76
Desirable levels of atherogenic cholesterol for primary pre-
vention are <130 mg/dL for non-HDL-C and <100 mg/dL for
LDL-C. In very high-risk patients, the desirable levels are
<100 mg/dL for non-HDL-C and <70 mg/dL for LDL-C.
The designation of non-HDL-C treatment targets as 30 mg/
dL more than the LDL-C concentration is based on the as-
sumption that Bnormal^ VLDL-C concentration when triglyc-
erides are <150 mg/dL is typically <30 mg/dL, and when
triglycerides are elevated, VLDL-C is typically >30 mg/dL.
Support for these thresholds derives primarily from observa-
tional evidence showing low ASCVD incidence rates in
groups with levels in these ranges [23, 24•]. In observational
studies, each 1-mg/dL increment in triglyceride-rich lipopro-
tein cholesterol is associated with an increment in ASCVD
event risk at least as large as that for each 1 mg/dL increase
in LDL-C. The current guidelines from ACC/AHA however
do not set a goal LDL level for titration of therapy.
Unless contraindicated, first-line drug therapy for treatment
of elevated atherogenic cholesterol levels is a moderate-or
high-intensity statin (see Table 3). A moderate-intensity statin
will generally lower LDL-C by 30 to <50 % and a high-
intensity statin by approximately 50 %, although individual
patient responses should be expected to vary considerably. In
some patients taking high-intensity statin therapy, atherogenic
cholesterol levels may drop to low levels (e.g., LDL-C ≤
40 mg/dL). At present, no evidence suggests harm with such
low circulating cholesterol levels, and therapy may be contin-
ued in such patients, particularly those at very high ASCVD
event risk, in the absence of signs or symptoms of intolerance.
High-intensity statin therapy should be initiated for adults
≤75 years of age with clinical ASCVD who are not receiving
statin therapy, or the intensity should be increased in those
receiving a low- or moderate-intensity statin, unless they have
a history of intolerance to high-intensity statin therapy or other
characteristics that could influence safety. When characteris-
tics predisposing to statin-associated adverse effects are pres-
ent, moderate-intensity statin should be used as the second
option, if tolerated. In individuals older than 75 years of age,
there is no clear benefit of using high-intensity statin therapy
compared to moderate-intensity statin. Hence moderate-
intensity statin therapy should be considered in these individ-
uals if indicated and therapy should be individualized.
The 2013 ACC/AHA guidelines also recommend high-
intensity statin therapy for individuals ≥21 years of age with
primary hypercholesterolemia due to lifetime exposure from
genetic causes. High-intensity statin therapy might not be ad-
equate to lower LDL-C sufficiently to reduce ASCVD event
risk in individuals with primary severe elevations of LDL-C.
In addition to a maximally tolerated dose of statin, nonstatin
cholesterol-lowering medications are often needed to lower
LDL-C to acceptable levels in these individuals. Because the
hypercholesterolemia in these high-risk individuals is often
genetically determined, family screening is especially
Page 5 of 10 76
important in this group to identify additional family members
who would benefit from assessment and early treatment.
Secondary causes of severe elevations of LDL-C ≥190 mg/
dL and triglycerides ≥500 mg/dL (e.g., excessive alcohol in-
take, uncontrolled diabetes, overt albuminuria) often contrib-
ute to the magnitude of the hyperlipidemia and should be
evaluated and treated appropriately.
Lipid Lowering Therapy Beyond Statins
For patients with very high triglycerides (>500 mg/dL), the
primary objective of therapy is to lower the triglyceride level
to <500 mg/dL to reduce the risk of pancreatitis. For patients
with hypertriglyceridemia who have high triglycerides (200–
499 mg/dL), the primary objective of therapy is to lower levels
of atherogenic cholesterol (non-HDL-C and LDL-C) to reduce
risk for an ASCVD event by using statins. ADA clinical prac-
tice guidelines note that combination therapy (statin/fibrate
and statin/niacin) has not been shown to provide additional
CV benefit above statin therapy alone [25•, 26•].
Epidemiologic evidence suggests that HDL-C is inversely
associated with ASCVD and the level of HDL-C is widely
accepted as an important risk indicator. Low HDL-C is also
a component of the metabolic syndrome. HDL particles have
several properties that are expected to provide protection
against ASCVD including reverse cholesterol transport, anti-
oxidation, endothelial protection, antiplatelet activity, and
anticoagulation, but a direct mechanistic relationship between
low HDL and ASCVD is not fully understood. To date, clin-
ical trials of agents that markedly raise HDL-C, including
niacin and cholesteryl ester transfer protein inhibitors, have
failed to demonstrate that they reduce all-cause mortality,
CHD mortality, myocardial infarction, or stroke in statin-
treated patients [27, 28, 29•]. Apolipoprotein B may be an
optional optional secondary target for treatment particularly
in patients with high triglyceride levels and low HDL-C levels
[30, 31]. This is particularly relevant when statin therapy
lowers cholesterol concentration more than the apo B level,
which is a potential contributor to residual ASCVD risk.
Clinicians may also consider measuring LDL particle concen-
tration as an alternative to apo B.
Newer Lipid Lowering Agents
In July 2015, the US Food and Drug Administration (FDA)
approved alirocumab (Praluent), the first in a new class, the
proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhib-
itors. PCSK-9 is part of the proteinase K subfamily of
subtilases and plays a key role in lipid metabolism. It increases
degradation of the low-density lipoprotein receptor (LDL-R),
modulates cholesterol metabolism and transport, and contrib-
utes to the production of apolipoprotein B (apoB) in intestinal
cells. Statins increase PCSK9 messenger RNA expression and
76 Page 6 of 10
attenuate the capacity to increase LDL-R levels. Therefore, the
inhibition of PCSK9 in combination with statins provides a
promising approach for lowering low-density lipoprotein cho-
lesterol (LDL-C) concentrations.
Alirocumab, a monoclonal antibody that inhibits
proprotein convertase subtilisin–kexin type 9 (PCSK9), when
administered subcutaneously every 2 weeks has been shown
to reduce low-density lipoprotein (LDL) cholesterol levels in
patients who are receiving statin therapy [32•]. In this random-
ized trial involving 2341 patients at high risk for cardiovascu-
lar events who had LDL cholesterol levels of 70 mg per deci-
liter (1.8 mmol per liter) or more and were receiving treatment
with statins at the maximum tolerated dose (the highest dose
associated with an acceptable side-effect profile), with or
without other lipid-lowering therapy there was evidence of
reduction in rate of cardiovascular events as well in a post
hoc analysis. Larger and longer-term studies are needed to
establish safety and efficacy however.
Dyslipidemia and Diabetes
The most typical lipoprotein pattern in diabetes, also known as
diabetic dyslipidemia or atherogenic dyslipidemia, consists of
moderate elevation in triglyceride levels, low HDL cholesterol
values, and small dense LDL particles. This lipoprotein pat-
tern is associated with insulin resistance and is present even
before the onset of diabetes. Small dense LDL particles are
highly atherogenic because of their enhanced susceptibility to
oxidative modification and increased uptake by the arterial
wall. In addition about 40 % of patients with diabetes have
elevated triglyceride levels (>200 md/dl) and 10 % with levels
greater than 400 mg/dl. LDL cholesterol remains the strongest
independent predictor of ASCVD followed by HDL in the
individual with diabetes [33].
Subgroup analyses of intervention trials using statins sug-
gest that the relative cardiovascular benefit of statins is similar
among diabetic and nondiabetic participants. The strongest
evidence for the beneficial effect of cholesterol lowering with
statins in diabetic individuals with and without evidence of
CVD and average cholesterol values comes from the Heart
Protection Study (HPS) [34] and the Collaborative
Atorvastatin Diabetes Study (CARDS) [35], the first statin
trials conducted in diabetic subjects. The HPS included 5963
diabetic individuals, 2912 of whom had no known CVD. All
subjects were >40 years of age. Treatment with 40 mg of
simvastatin reduced the risk of major CHD by 27 %. In
CARDS, 2383 individuals (mean age 62 years, mean LDL
cholesterol 118 mg/dl) with diabetes but no CVD and at least
one risk factor, including hypertension, smoking, retinopathy,
and micro- or macroalbuminuria, were randomized to atorva-
statin 10 mg per day versus placebo. Treatment with atorva-
statin resulted in a 36 % reduction in acute cardiac events and
Curr Hypertens Rep (2016) 18:76
a 48 % reduction in stroke after a median 3.9 years of follow-
up. The study was prematurely ended because of the early
positive results. The relative benefit of atorvastatin was similar
in individuals whose baseline LDL cholesterol was <120 mg/
dl and those with LDL cholesterol >120 mg/dl.
In patients with diabetes who are aged >40 years, without
overt CVD, the new ACC/AHA cholesterol guidelines indi-
cate that there is strong evidence that moderate-intensity statin
therapy should be initiated or continued for adults 40–75 years
of age, or high-intensity statin if the individual calculated risk
is high (≥7.5 % estimated 10-year atherosclerotic cardiovas-
cular disease [ASCVD] risk using the pooled cohort equa-
tions. In persons with diabetes who are <40 years of age or
>75 years of age or whose LDL-C is <70 mg/dl, statin therapy
should be individualized on the basis of considerations of
ASCVD risk-reduction benefits, the potential for adverse ef-
fects and drug-drug interactions, and patient preferences. It is
important to recognize that the results of statin interventions in
patients with diabetes have demonstrated that the observed
benefits were independent of baseline LDL-C and other lipid
values.
Clinical trials conducted to date do not support triglyceride
reduction in the presence or absence of diabetes as a means to
reduce CVD risk. Four major fibrate trials in which patients
with CHD and/or diabetes have been included have been com-
pleted. The VA-HIT (Department of Veterans Affairs High-
Density Lipoprotein Intervention Trial) was carried out in men
with known CVD and low levels of HDL-C (<40 mg/dl), and
gemfibrozil was the fibrate chosen. The VA-HIT was the only
fibrate study to demonstrate a significant benefit of a fibrate on
CVD, an effect mostly demonstrated in the 25 % of patients
with diabetes.
Dyslipidemia in the Hypertensive Patient
There is evidence from clinical trial data that suggests a syn-
ergy between blood-pressure control and lipid lowering. The
first demonstration of a positive interaction between simva-
statin and antihypertensive agents was published by Sposito
et al. [36]. This group reported the results obtained from a
small population of patients with hypertension and high serum
total cholesterol in which the antihypertensive effect of enal-
april or lisinopril was significantly enhanced by the concom-
itant administration of pravastatin or lovastatin. Because of the
multiplicative effects of risk factors such as dyslipidemia in
the presence of hypertension special attention should be given
when making pharmacologic choices in managing high blood
pressure.
While thiazide diuretics have been advocated as initial ther-
apy in most patients with hypertension, based on data from
ALLHAT, we have to pay attention to the potential lipid ab-
normalities that may occur and affect overall cardiometabolic
risk [37]. The ALLHAT trial was a long-term, multicenter trial
Curr Hypertens Rep (2016) 18:76
that included 42,418 participants aged 55 and older with stage
1 or stage 2 hypertension and at least one other cardiovascular
disease risk factor. The mean fasting serum glucose levels at
baseline were 123.5, 123.1, and 122.9 mg/dL (6.9, 6.8, and
6.8 mmol/L); at 4 years, the mean levels were 126.3, 123.7,
and 121.5 mg/dL (7.0, 6.9, and 6.7 mmol/L) in the
chlothalidone, amlodipine, and lisinopril groups respectively.
The chlorthalidone group had more hypokalemia, higher
mean serum cholesterol and glucose levels, and higher inci-
dence of new cases of diabetes at 4-years follow-up. The com-
parison of the lisinopril and chlorthalidone groups showed
statistical significance (p < 0.05). Among individuals classi-
fied as nondiabetic at baseline, with baseline fasting serum
glucose less than 126 mg/dl (7.0 mmol/L), incidence of dia-
betes (fasting serum glucose >126 mg/dl) at 4 years was 11.6,
9.8, and 8.1 %, respectively. Both comparisons with the
chlorthalidone group were statistically significant at p < 0.05.
Echoing the results from ALLHAT, data from the ASCOT-
BPLA showed that treatment with traditional anti-
hypertensive therapy was associated with significantly higher
incidence of new-onset diabetes and attendant dyslipidemia as
compared to contemporary therapy with ACEI-I and CCB.
The Anglo-Scandinavian Cardiac Outcomes Trial—Blood
Pressure Lowering Arm (ASCOT-BPLA) was a multicenter,
prospective, randomized controlled trial that enrolled 19,257
patients (age, 40–79 years) with hypertension [38]. Patients
were randomly assigned to either amlodipine 5–10 mg adding
perindopril 4–8 mg (n = 9639) or atenolol 50–100 mg adding
bendroflumethiazide 1.25–2.5 mg and potassium as required.
Both regimens significantly lowered blood pressure (BP),
with amlodipine reducing systolic BP an additional 2.7/
1.9 mmHg on average compared with atenolol (p < 0.0001).
This difference would have been expected to result in 4 %
fewer coronary events, and 11–14 % fewer strokes.
However, amlodipine reduced nonfatal myocardial infarction
(excluding silent MI) and coronary heart disease by 13 %,
total cardiovascular disease events and procedures by 16 %,
total coronary events by 13 %, all-cause mortality by 11 %,
cardiovascular mortality by 24 %, and fatal and nonfatal
stroke by 23 % compared with atenolol. In addition, the
amlodipine-based regimen was associated with a significantly
lower risk for the new onset of diabetes.
The value of ACE inhibitors and ARBs in hypertensive
patients with the metabolic syndrome who do not have CVD
or diabetes is not clear. Several large clinical trials on hyper-
tension such as the Losartan Intervention For Endpoint (LIFE)
reduction in hypertension study and the Heart Outcomes
Prevention Evaluation (HOPE) study which used ramipril in
patients at high risk of cardiovascular events have shown the
benefit of RAAS blockade with angiotensin-converting en-
zyme inhibitors (ACE-I) and angiotensin receptor blockers
(ARB) by demonstrating lower incidence of new-onset diabe-
tes mellitus [39, 40]. In the NAVIGATOR study, a single daily
Page 7 of 10 76
dose of the ARB valsartan (up to 160 mg), when added to
lifestyle intervention reduced the risk of diabetes but not of
cardiovascular events in patients with impaired glucose toler-
ance and established cardiovascular disease or risk factors.
The relative reduction of 14 % in the risk of diabetes in the
valsartan group was consistent across all subgroups that were
examined [41]. Animal studies have shown improvement in
insulin resistance, reduction of ROS production, and increased
mitochondrial biogenesis with enalapril and losartan [42, 43].
Studies have also shown significant increase in adiponectin
levels with inhibition of RAAS with ACEI or ARB, which is
associated with improved insulin sensitivity [44]. ACEI and
ARBs might increase peroxisome proliferators-activated re-
ceptor (PPARγ) activity which might promote adipogenesis
thus improving metabolic perturbations [45].
Dyslipidemia in the Patient with the Metabolic Syndrome
Obesity is an important aspect of the metabolic syndrome
apart from dyslipidemia and hyperglycemia. Majority of the
patients with obesity have trouble losing weight or regain
weight quickly after losing it with caloric restriction and in-
creased physical activity. There have been attempts to develop
medications that can cause weight loss. Various medications
have been tried in the past and new medicines or combinations
have recently been used to achieve weight loss.
Metabolic benefits associated with sibutramine-induced
weight loss were reported by Krejs et al. [46]. Sibutramine
was subsequently withdrawn from the market due to increased
incidence of stroke and myocardial infarction [47]. Similarly,
fenfluramine which showed efficacy for weight loss was with-
drawn due to association with valvular heart disease and pul-
monary hypertension with its use [48, 49]. Orlistat has been
shown in a few studies to improve individual components of
metabolic syndrome in addition to promoting weight loss and
mobilizing visceral fat [50, 51]. The problem with this drug
continues to be a relatively high rate of adverse side effects
leading to poor compliance.
The discovery of the endocannabinoid system and its role
in feeding and energy balance promised the potential of a new
therapeutic approach to the problem of insulin resistance and
obesity. Endocannabinoids act at the CB1 receptors to in-
crease hunger and promote feeding and it is speculated that
they decrease intestinal peristalsis and gastric emptying. Thus,
antagonism at these receptors can inverse these effects [52].
Inhibition of CB1 with rimonabant in humans is associated
with weight loss, reduced waist circumference, improvements
in atherogenic dyslipidemia, blood pressure, glycemia, and
adiponectin levels. Antagonism of CB1 receptors in peripher-
al tissues increases insulin sensitivity and oxidation of fatty
acids in muscles and the liver [53]. The first CB1 antagonist
Rimonabant, which was developed and marketed is no longer
in use due to neuro-psychiatric adverse effects. A number of
76 Page 8 of 10
attempts have been initiated to develop CB1 antagonists that
target only peripheral CB1 receptors by restricting their ability
to cross the blood brain barrier to avoid the side effects that
were noted with Rimonabant.
Other medications recently approved by the Food and
Drug Administration for the treatment of obesity include
pherntermine/topiramate, liraglutide, and naltrexone/
buproprion [54–56]. The phentermine/topiramate combi-
nation was the first drug approved for the long-term man-
agement of obesity [57]. Phentermine is a sympathomi-
metic amine which blocks reuptake of norepinephrine to
suppress appetite and increase energy expenditure.
Topiramate, which was initially released as an anti-
epileptic agent causes weight loss by altering nerupeptide
Y levels thus reducing appetite. Clinical trials with this
combination have shown weight loss between 7.5 and
9.3 %. While no major cardiovascular events have been
associated with the use of this combination, the heart rate
does increase and should not be used with recent coronary
syndromes. The naltrexone/bupropion combination is
comprised of a μ-opioid receptor antagonist and a dopa-
mine and norepinephrine reuptake inhibitor. Naltrexone is
approved as monotherapy for opioid addiction and alco-
hol dependence, whereas bupropion is approved as mono-
therapy for depression, smoking cessation, and seasonal
affective disorder [58]. The mechanism of action of the
combination relates to complex central pathways of re-
ward and satiety. Use of this combination achieved weight
loss of 2.5–5.2 % of initial body weight compared to
placebo in the Contrave Obesity Research trials [59–61].
Naltrexone/bupropion is contraindicated in patients with
uncontrolled hypertension but can otherwise be prescribed
to patients with known cardiovascular disease. Liraglutide
is a glucagon-like peptide (GLP)-1 receptor agonist.
Liraglutide exerts its action through binding the GLP-1
receptor on pancreatic beta cells, increasing their sensitiv-
ity to glucose. Originally approved for the treatment of
type 2 diabetes mellitus on the basis of the LEAD
(Liraglutide Effect and Action in Diabetes) series of trials,
liraglutide was noted to promote significant weight loss
[62]. Liraglutide was approved by the FDA in 2014 for
the treatment of obesity in patients with a body mass
index (BMI) >30 or >27 kg/m2 with an obesity-related
comorbidity and can be used in patients with known car-
diovascular disease.
When comparing the weight loss seen with these med-
ications, any improvement in cardiometabolic parameters
induced by them are less than similar weight loss
achieved by non-pharmacological means. In terms of gly-
cemic measures, only liraglutide potentially produces an
improvement in HbA1c over a similar degree of
nonpharmacological weight loss. Beneficial changes in
lipid profile are also marginal though both liraglutide
Curr Hypertens Rep (2016) 18:76
and naltrexone/bupropion cause a slight increase in
HDL-C. The degree of blood pressure reduction seen is
commensurate with the loss in weight. However, there is a
paradoxical increase in heart rate with all pharmacological
agents in contrast to nonpharmacological weight loss. The
issue of concern is that available data on the weight loss
medications are limited to short-term effects of these
agents on weight loss alone with the exception of
liraglutide [63•]. No trial has specifically studied the ef-
fects of these agents at the approved doses for weight loss
on outcomes such as atherosclerosis, heart failure, coro-
nary artery disease, or diabetes. Nevertheless, there is ev-
idence to support the use of liraglutide over other agents
particularly in diabetic individuals. Moreover, naltrexone/
bupropion may have a particular role in treating obesity in
patients with alcohol or nicotine dependence.
Conclusion
Insulin resistance, hypertension, and endothelial dysfunc-
tion occur as a result of genetic predilections and environ-
mental influences and together lead to vascular inflamma-
tion. Vascular inflammation is characterized by athero-
sclerosis which is exaggerated by hyperlipidemia.
Dyslipidemia is one of the common link between hyper-
tension, metabolic syndrome, and diabetes. Lipid disor-
ders in these conditions consist of multiple abnormalities
including high triglycerides, low HDL cholesterol, and
increased or normal LDL cholesterol with highly athero-
genic component referred as small dense LDL cholesterol.
Several of these abnormalities are related to the underly-
ing insulin resistance, the common link between hyperten-
sion, metabolic syndrome, and diabetes. Because of this,
management of hyperlipidemia is an important aspect of
therapy as it can prevent the progression of atherosclero-
sis and the related macrovascular events such as MI and
stroke. However, it is important to emphasize that the
intervention strategies should always incorporate multi-
factorial risk management. The primary component of this
strategy should be lifestyle modification, which includes
dietary adjustments and physiologic exercise patterns for
a healthy life style. Secondary component of management
is pharmacologic interventions.
Compliance with Ethical standards
Conflict of Interest Drs. Srikanth and Deedwania declare no conflicts
of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Curr Hypertens Rep (2016) 18:76
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