Editors: Sabatine, Marc S.

Title: Pocket Cardiology, 2nd Edition

Copyright ©2023 Lippincott Williams & Wilkins

> Table of Contents > Preventive Cardiology

Preventive Cardiology

HYPERTENSION

ACC/AHA Classification for Office-Based BP (HTN 2018;71:e13)

Category Systolic (mmHg) Diastolic (mmHg)

Normal <120 <80

Elevated 120-129 <80

Stage 1 hypertension 130-139 80-89

Stage 2 hypertension ≥140 ≥90

Categories based on SPRINT trial (NEJM 2015;373:2103). Nb, ESC, & ISH define HTN as office-based SBP ≥140 or
DBP ≥90 mmHg.

If disparity in a category between systolic and diastolic, higher value determines stage

Average ≥2 measurements >1-2 mins apart

Confirm stage 1 within 1-4 wks; can treat stage 2 immediately

[check mark] q2y (if normal) or yearly (if elevated)

Ambulatory Thresholds for Hypertension

Setting Systolic (mmHg) Diastolic (mmHg)

24-hr mean ≥125 ≥75

Day* (awake) ≥130 ≥80

Night (asleep) ≥110 ≥65

 *
Threshold of hypertension for home readings should be same as daytime ambulatory on a 24-hour
ambulatory monitor (see below). ESC uses 24-hour mean ≥130 systolic or ≥80 diastolic or a daytime
mean ≥135 systolic or ≥85 diastolic (EHJ 2018;39:3021).

Correlation of SBP & DBP by Mode of Measurement (HTN 2018;71:e13)

Clinic Home Monitor Daytime ABPM Nighttime ABPM 24-hour ABPM

120/80 120/80 120/80 100/65 115/75

130/80 130/80 130/80 110/65 125/75

140/90 135/85 135/85 120/70 130/80

160/100 145/90 145/90 140/85 145/90

Measurement & diagnosis

Measure yearly in adults with normal BP and semiannually if elevated or risk factors

Avoid caffeine, exercise, or smoking 30 min prior; take BP w/ Pt sitting w/ feet on floor

First visit measure in both arms

Automated cuff more accurately predicts awake ABPM vs. traditional manual (JAMA IM 2019;179:351)

Obtain after 5 min of rest, ≥2 times, 1-2 mins apart, reporting average

Elevated office BP should be confirmed with out-of-office (ABPM or home cuff) to confirm

White coat (≥ Stage 1 in office but < at home) at heightened risk of developing HTN

Masked (< Stage 1 in office but ≥ at home), if persistent, treat as hypertension

24-hr ambulatory BP preferred method for confirming HTN (including white coat & masked)

Epidemiology (Circ 2021;143:e254)

Prevalence: 47% in U.S. adults; >121 million affected (prevalence equal for men and women, highest in African
American adults at ˜58%)

↑ Age → ↓ arterial compliance → systolic HTN

39% of U.S. adults are not aware they have HTN and only 48% of Pts with dx of HTN have adequate BP control

Primary hypertension
Accounts for 95% of cases

Onset typically 25-55 years of age

 Unclear mechanism but ? additive microvascular renal injury over time w/ contribution of hyperactive
sympathetics (NEJM 2002;346:913)

Risk factors include age, obesity, diet (Na intake), alcohol, physical inactivity, FHx (JAMA 2009;302:401)

Genetic predisposition (Nature 2011;478:103)

Blacks more likely to be salt sensitive and have less activation of renin-angiotensin system, explaining
preference for thiazides & CCB over ACEI or ARB

P.20

Secondary hypertension
Consider if Pt <20 or >50 years old or if sudden onset, severe, refractory HTN

Secondary Causes of Hypertension

Diseases Suggestive Findings Initial Workup

Renal parenchymal (2-3%) h/o DM, polycystic eGFR,

kidney disease, albuminuria
glomerulonephritis

Renovascular (1-2%, qv) ARF induced by MRA (>90% Se &

RENAL ACEI/ARB Sp, less for
Recurrent flash pulm FMD), CTA,
Athero (90%) edema duplex U/S,
FMD (10%, Renal bruit; angio, plasma
women) hypokalemia (NEJM renin (low Sp)
PAN, 2009;361:1972)
scleroderma

Hyperaldo or Cushing’s (1-5%) Hypokalemia

Metabolic alkalosis

See below

Pheochromocytoma Paroxysmal HTN, H/A, palp.

(<1%)

ENDO
Hypothyroidism (<1%) Weakness, fatigue, TFTs
cold intolerance,
constipation

Hypercalcemia (<1%) Polyuria, iCa

dehydration, Δ MS

OTHER Obstructive sleep apnea (qv)

Medications: OCP, steroids, licorice, NSAIDs, decongestants, Epo, cyclosporine, oncologic

therapies, angio inhibitors (bevacizumab) & TKIs (eg, sunitinib), illicit drugs
 Aortic coarctation: ↓ LE pulses, systolic murmur, radial-femoral delay; abnl TTE, CXR

Polycythemia vera: ↑ Hct

Adrenal disorders as secondary causes

Hyperaldosteronism

Etiologies: 1° (adrenal disorders), 2° (renin-dependent, typically from RAS [qv]), or nonaldo mineralocorticoid
excess (11β-HSD deficiency, black licorice, Liddle’s syndrome)

Clinical: headache, muscle weakness, polyuria, polydipsia; no peripheral edema; classically hypokalemia (but
often normal), metabolic alkalosis, mild hypernatremia

Diagnosis: aldo (>15-20 ng/dL) and plasma aldo:renin ratio (>20 if 1°). Obtain 8 a.m. paired values, Se & Sp
>85%. Must be off spironolactone & eplerenone for 6 wks. ACEI/ARB, diuretics, CCB, & βBs can Δ PAC/PRA
ratio; avoid. α-blockers generally best to control HTN during dx testing. Confirm with sodium suppression
test (fail to suppress aldo after sodium load).

Hypercortisolism

Etiologies: Cushing’s disease (ACTH-secreting pituitary adenoma or hyperplasia), adrenal tumor, ectopic ATCH
(eg, lung cancer)

Clinical: glucose intolerance or DM, central obesity, dorsocervical fat pads, proximal myopathy, rounded
facies, wide purple striae, oligo- or amenorrhea, osteoporosis

Diagnosis: dexamethasone suppression test or 24-hour urinary free cortisol; if , ACTH

Pheochromocytoma

Etiologies: neuroendocrine neoplasm

Clinical (the 5 P’s): pressure (hypertension, paroxysmal in 50%), pain (headache, chest pain), palpitations
(tachycardia, tremor, wt loss, fever), perspiration, pallor (vasoconstrictive spell)

Diagnosis: 24° urinary fractionated metanephrines (85-97% Se, 69-95% Sp; screening test of choice if low risk)
or plasma-free metanephrines (89-100% Se, 79-97% Sp; screening test of choice if high risk); if then adrenal
CT

Standard workup (HTN 2018;71:e13)

Goals

1. Identify CV risk factors or other diseases that would modify prognosis or Rx

2. Reveal 2° causes of hypertension

3. Assess for target-organ damage

History: CAD, HF, TIA/CVA, PAD, DM, renal insufficiency, sleep apnea, preeclampsia; FHx for HTN; diet, Na
intake, smoking, alcohol, prescription and OTC meds, OCP

Physical exam: funduscopic exam; BMI & waist circumference; cardiac (LVH, murmurs) including signs of HF,
vascular (bruits, radial-femoral delay); abdominal (masses or bruits); neuro exam

Testing: K, BUN, Cr, Ca, glc, Hct, U/A, lipids, TSH, urinary albumin:creatinine (if ↑ Cr, DM, or peripheral
edema), ? renin, ECG (for LVH), CXR, TTE (eval for valve abnl, LVH)

Ambulatory BP monitoring (ABPM): predictive of CV risk and ↑ Se & Sp for dx of HTN vs. office BP (HTN
2005;46:156). Consider for suspected episodic or white coat HTN, resistant HTN, HoTN sx on meds, or
 suspected autonomic dysfxn. Recommended by some guidelines to confirm HTN dx, so utilization may expand
(BMJ 2011;342:d3621 & 343:d4891).

P.21

Complications of HTN
Each ↑ 20 mmHg SBP or 10 mmHg DBP associated with 2× ↑ CV complications (Lancet 2002;360:1903)

Systolic hypertension more predictive of adverse outcomes but diastolic also important (J-curve relationship)
with consistent relationship at lower thresholds (NEJM 2019;381:243)

LVH and heart failure (JAMA 1996;275:1557)

Neurologic: TIA/CVA, ruptured aneurysms, vascular dementia

Retinopathy: stage I = arteriolar narrowing; II = copper wiring, AV nicking; III = hemorrhages and exudates; IV =
papilledema

Cardiac: CAD, AF

Vascular: aortic dissection, aortic aneurysm (HTN = key risk factor for aneurysms)

Renal: proteinuria, renal failure

TREATMENT
Overview (HTN 2018;71:e13)
Goal: in general, <130/<80 mmHg
However, for low CV risk Pts, more liberal targets can be considered (eg, <135/<85 out-of-
office or <140/<90 in-office)

Lifestyle modification
Should be used in all patients; each can ↓ SBP ˜5 mmHg
Weight loss: goal BMI 18.5-24.9 with benefit independent and synergistic with sodium
restriction; aerobic exercise: ≥30 min exercise/d, ≥5 d/wk
Diet: rich in fruits & vegetables, low in saturated & total fat (DASH, NEJM 2001;344:3)
Sodium restriction: ≤2.4 g/d and ideally ≤1.5 g/d (NEJM 2010;362:2102); benefit even
with modest salt moderation for ≥4 weeks (BMJ 2013;346:325)
Maintain adequate potassium intake through diet counseling (˜120 mEq of dietary
potassium) if no predisposition to hyperkalemia (NEJM 2007;356:1966)
Limit alcohol consumption: ≤2 drinks/d in ♂; ≤1 drink/d in ♀ & lighter-wt Pts
Avoid exacerbating exposures (eg, NSAID use)

Pharmacologic therapy
Typically lowers SBP by ˜5 mmHg. Each 5 mmHg ↓ in SBP results in ˜10% ↓ in risk of
ischemic heart disease, stroke, and HF (Lancet 2021;397:1625).
Indicated if:
office BP≥130/80 and ASCVD, HF, CKD, T2DM, ≥65 yrs old, or 10-yr ASCVD risk ≥10%
office BP≥140/90 or ambulatory BP≥135/85
Elevated (previously “pre-HTN”) w/o any of the above features treated w/ lifestyle alone.
ARB prevents onset of HTN, no ↓ in clinical events (NEJM 2006;354:1685).
Choice of drug: concomitant disease and stage may help guide Rx

Uncomplicated: CCB, ARB or ACEI, or thiazide (chlorthalidone preferred) is 1st line (NEJM
2009;361:2153); βB not 1st line (Lancet 2005;366:1545).
For non-Black Pts <60 y: reasonable to start w/ ARB or ACEI, then add CCB or thiazide if
needed, and then add remaining class if still needed
 For Black, elderly, and ? obese Pts (all of whom more likely to be salt sensitive):
reasonable to start with CCB or thiazide, then add either the other 1st choice class or ARB
or ACEI if needed, and then all 3 classes if still needed
CAD (Circ 2015;131:e435): ACEI or ARB (NEJM 2008;358:1547); ACEI+CCB superior to
ACEI+thiazide (NEJM 2008;359:2417) or βB+diuretic (Lancet 2005;366:895); may require
βB and/or nitrates for anginal relief; if h/o MI, βB ± ACEI/ARB ± aldo antag (see “ACS”)
HF: ARNI/ACEI/ARB, βB, diuretics, aldosterone antagonist (see “HFrEF” & “HFpEF”)
2° stroke prevention: ACEI (Lancet 2001;358:1033); ? ARB (NEJM 2008;359:1225)
Diabetes mellitus: ACEI or ARB; can also consider thiazide or CCB
Chronic kidney disease: ACEI or ARB (NEJM 1993;329:1456 & 2001;345:851 & 861)
Tailoring therapy
Lifestyle Δs typically complementary rather than alternative to drug Rx (although if low risk
[stage 1, no end-organ damage or risk factors], could start with lifestyle)
If stage 1, start w/ monoRx; if stage 2, consider starting w/ combo (eg, ACEI + CCB; NEJM
2008;359:2417), as most will require ≥2 drugs
typically start drug at ½ maximal dose; after 2-3 wk either titrate up or add new drug
Combination therapy: if SBP ≥15 mmHg above goal, consider combo Rx (ACEI/ARB +
either CCB or chlorthalidone). Recommended to start with combo Rx if ≥20 mmHg above
SBP goal or ≥10 mmHg above DBP goal.
Pregnancy: methyldopa, labetalol, nifedipine, hydralazine; avoid diuretics; Ø ACEI/ARB

P.22
Resistant hypertension (JAMA 2014;311:2216)
BP > goal on ≥3 drugs incl diuretic; ˜12-13% of hypertensive population (HTN
2011;57:1105)
Differentiate between true & pseudoresistance, w/ latter due to:
inaccurate measurement or use of wrong cuff size
poor dietary compliance (Na/K intake, can assess w/ 24-hr urine for Na, K, and Cr)
suboptimal med dosing (eg, <50% of max dose) or poor med compliance
volume expansion (inadequate diuretic dosing)
white coat HTN (confirm with ABPM)
2° causes or external drivers (eg, OSA, steroids, NSAIDs, alcohol, certain cancer therapies)
(Lancet 2010;376:1903)
True resistance = uncontrolled BP confirmed by ABPM despite compliance w/ optim. doses
Treatment considerations:
Ensure volume status well controlled as may contribute even if on standard HCTZ
(Archives 2008;168:1159). Effective diuretic dosing required for most to achieve control
(HTN 2002;39:982). Chlorthalidone over HCTZ (if renal function preserved). Loop diuretic
favored over thiazide for initial Rx if eGFR <30; however, adding thiazide to loop can ↑
diuresis if insufficient response to loop alone.
Adding aldosterone antagonist (if renal function preserved) (Lancet 2015;386:2059)
Adding β-blocker (particularly vasodilating ones such as labetalol, carvedilol, or nebivolol),
centrally acting agent, α-blocker, or direct vasodilator
Other Rx under investigation: renal denervation (see below); carotid baroreceptor
stimulation; central AV anastomosis ↓ SBP by ˜23 mmHg (Lancet 2015;385:1634)
Renal denervation: catheter-based RF ablation of renal nerves modifying sympathetic
outflow. Had appeared beneficial in unblinded and/or uncontrolled studies, but no effect on
BP in one sham-controlled trial in Pts with uncontrolled HTN (NEJM 2014;370:1393). More
recent sham-controlled trial in Pts w/ HTN not on meds showed ˜4 mmHg ↓ in 24-hr SBP
and 6.5 mmHg ↓ in office-based SBP (SPYRAL HTN-OFF MED, Lancet 2020;395:1444).
HYPERTENSIVE CRISES (NEJM 2019;381:1843)
Definitions
Hypertensive emergency: ↑ BP → acute target-organ ischemia and damage
Neurologic: encephalopathy (insidious onset of headache, nausea, vomiting, confusion),
hemorrhagic or ischemic stroke (˜40%), papilledema
Cardiac: ACS, HF/pulmonary edema (˜30%), aortic dissection (<5%)
Renal: proteinuria, hematuria, acute renal failure; scleroderma renal crisis
Microangiopathic hemolytic anemia; preeclampsia-eclampsia
Hypertensive urgency (severe asymptomatic HTN): SBP >180 or DBP >120 (?110)
w/ minimal or no target-organ damage. Presentation diagnostic of hypertension.

Precipitants
Progression of essential HTN ± medical noncompliance (espec. clonidine) or Δ in diet

Progression of renovascular disease; acute glomerulonephritis; scleroderma; preeclampsia

Endocrine: pheochromocytoma, Cushing’s

Sympathomimetics: cocaine, amphetamines, MAO inhibitors + foods rich in tyramine

Cerebral injury: do not treat HTN in acute ischemic stroke unless Pt getting lysed, extreme BP (>220/120), Ao
dissection, active ischemia or HF (Stroke 2003;34:1056)

Workup
ECG, CXR, basic metabolic panel, UA, cardiac biomarkers, selected imaging (head CT or MRI if neuro sx,
nausea or vomiting; chest CT if sx of dissection or pulse deficit)

P.23

Treatment—tailor to clinical condition (Circ 2018;138:e426)

AoD, eclampsia/severe preeclampsia, pheo: target SBP <140 (<120 for AoD) in 1 hour

Emerg w/o above: ↓ BP by ˜25% in 1 h; to 160/100-110 over next 2-6 h, then nl over 1-2 d

Acute ischemic stroke (within 72 hrs from sx onset): <185/110 before lysis planned, o/w target <220/120
(same SBP goal for ICH)

Watch UOP, Cr, mental status: may indicate a lower BP is not tolerated

IV Drugs for Hypertensive Emergency (Circ 2018;138:e426; Stroke 2018;49:46)

Drug Dose Preferred for

Labetalol 20-80 mg IVB q10min or 0.4-2 mg/min AoD, ACS, stroke, eclampsia

Esmolol 0.5-1 mg/kg load → 50-200 µg/kg/min AoD, ACS

Nitroprusside* 0.25-10 µg/kg/min Pulm edema

Nitroglycerin 5-500 µg/min Pulm edema, ACS

Nicardipine 5-15 mg/h (can ↑ 2.5 mg/h q 5 min) Stroke, AKI, eclampsia, pheo

Clevidipine 1-32 mg/h (can titrate q 5-10 min) Stroke, pulm edema, AKI, pheo

Fenoldopam 0.1-1.6 µg/kg/min AKI

Hydralazine 10-20 mg q20-30min prn Eclampsia

Phentolamine 5-15 mg bolus q5-15min Pheo

Enalaprilat 1.25-5 mg q6h

*
Metabolized to cyanide →Δ MS, lactic acidosis, death. Limit use of very high doses (8-10 µg/kg/min)
to <10 min.

Monitor thiocyanate levels. Hydroxocobalamin or sodium thiosulfate infusion for treatment of cyanide
toxicity.

Treatment Considerations for Specific Clinical Settings

Clinical Setting Note Treatment

Acute stroke BP ↓ must be balanced Consult stroke team; may tolerate

w/risk of worsening BP up to 185/110
ischemia

Aortic dissection (qv) [check mark] BP in both βB first, then add vasodilator (eg,
arms and treat higher nitroprusside) if needed. Target
value systolic <100-120 mmHg; HR ≤ 60
bpm.

Acute pulm edema Avoid inotropes (eg, Vasodilator (eg, NTG) and loop
βB) if LV dysfxn, unless diuretic
ischemia

Antihypertensive Suspect if abrupt d/c of Restart d/c’d drug or consider

withdrawal symp. blocker (eg, labetalol or nitroprusside
clonidine)
 Sympathetic activity (pheo, Avoid βB as could → Phentolamine
autonomic dysfxn, cocaine, unopposed α in (pheochromocytoma),
MAO + tyramine-containing vasculature → nitroprusside
foods) vasoconstriction and
further ↑ BP

Renal emergency (acute Hematuria may be Consult renal team; fenoldopam

nephrosclerosis) present; acute lowering may ↓ risk of ↓ renal fxn (Crit Care
may worsen function 2015:19;449)

P.24

DYSLIPIDEMIA

Lipoproteins
Macromolecular complexes composed of lipids and proteins that serve to transport poorly soluble lipids
through the body

Core of hydrophobic lipids (triglycerides [TG] & cholesteryl esters) surrounded by shell of hydrophilic lipids
(phospholipids & unesterified cholesterol) and proteins (called apolipoproteins)

Includes: chylomicrons, chylomicron remnants, VLDL, IDL, LDL, Lp(a) (a subtype of LDL that has special
attributes, vide infra), HDL

Lipoprotein metabolism
Exogenous pathway: primarily TG along w/ apoB-48, apoC’s and apoE packaged into chylomicrons in
enterocytes and enter circulation via lymphatics & thoracic duct. Bring TG to adipocytes & myocytes where
lipoprotein lipase (LPL) hydrolyzes TG, liberating free fatty acids. As hydrophobic core depleted of TG,
resultant particles are called chylomicron remnants and rapidly taken up by the liver (via LDL receptor
[LDLR]).

Endogenous pathway: primarily TG along w/ cholesteryl esters, apoB-100, phospholipids, & vitamin E
packaged in liver by microsomal TG transfer protein (MTP) into VLDL and secreted into circulation. Bring TG to
adipocytes and myocytes where LPL hydrolyzes TG, liberating free fatty acids. Resultant particles, which now
have roughly equal amounts of TG and cholesterol, are called IDL. ˜½ IDL taken up by liver (via LDLR) and
other ˜½ remodeled by hepatic lipase (depleting TG and removing all apolipoproteins except apoB-100) to
form cholesterol-rich LDL. LDL taken up by liver via LDLR.

Reverse cholesterol transport: liver & intestine secrete nascent HDL containing unesterified cholesterol &
apoA1. Circulates and takes up unesterified cholesterol from cells, VLDL, or chylomicrons. Cholesterol
transported to liver either directly (HDL taken up by liver) or indirectly (cholesteryl esters transferred to VLDLs
[which become LDLs] in exchange for TG by cholesteryl ester transfer protein [CETP] and LDL cleared by
LDLR).

Thus, chylomicrons & VLDL are TG-rich lipoproteins that deliver energy to cells, LDL is a cholesterol-rich
lipoprotein that is the by-product of TG removal from VLDL, and HDL facilitates reverse cholesterol transport
and excretion

Lipid measurements
Lipoproteins can be measured by ultracentrifugation or NMR, but not done in routine practice. Instead, lipid
content of blood measured.

Total cholesterol (cholesterol in all lipoproteins) measured by enzymatic reaction

 TG (TG content in all lipoproteins; surrogate for concentration of TG-rich lipoproteins) measured by enzymatic
reaction; levels affected by eating, measure after 12-hr fast

HDL-C (cholesterol in HDL particles; surrogate for concentration of HDL particles) measured by enzymatic
reaction after removing apoB-containing particles

LDL-C (cholesterol in LDL particles; surrogate for concentration of LDL particles)

typically estimated by Friedewald equation: LDL-C = TC − HDL-C − (TG/5)

last term assumes TG:cholesterol ratio in VLDL particles is 5

as formula uses TG, should measure fasting (but underestimation typically <10 mg/dL)

levels stable up to 24 h after ACS and other acute illnesses, then ↓ and may take 6 wks to return to baseline
(“inverse acute phase reactant”)

underestimates true LDL-C if TG >400 or LDL-C <70 mg/dL

Martin-Hopkins formula more accurate (JAMA 2013;310:2061)

ideally directly measure LDL-C (direct assay or ultracentrifugation)

Non-HDL-C (TC − HDL-C) and apoB are alternative nonfasting measures of risk that better encompass all
atherogenic lipoproteins, are better risk predictors than LDL-C, and are increasingly being incorporated into
treatment guidelines

Metabolic syndrome
Constellation of metabolic abnormalities associated with ↑ risk of CV disease

May largely be driven by ↑ central adiposity → insulin resistance, ↑ TG, ↓ HDL-C, HTN

Consensus definition requires central adiposity + ≥2 other criteria (Circ 2009;120:1640) central obesity: waist
≥40″ (or 37″) in men or ≥35″ (or 31.5″) in women

TG >150 mg/dL

HDL <40 mg/dL in men or <50 mg/dL in women

SBP ≥130 or DBP ≥85 mmHg or dx of HTN

fasting glc ≥100 mg/dL or dx of DM

Lipoproteins and clinical risk

All apoB-containing lipoproteins (ie, LDL, IDL, VLDL) can promote atherogenesis; risk appears proportional to #
of particles, not chol. or TG content per se (JAMA 2019;321:364)

P.25
Imaging studies of coronary atheroma show growth when LDL-C exceeds ˜70 mg/dL and regression when below,
with rate of growth or regression proportional to how much LDLC is above or below that threshold (JAMA
2007;297:499)

High levels of TG (>500 mg/dL) can cause pancreatitis

More common primary dyslipidemias

Familial hypercholesterolemia (1:250): loss-of-fxn mutations in LDLR → ↓ LDL hepatic uptake & ↑↑ LDL-C in
circulation & ↑ risk of premature CAD. Familial defective apoB-100 (↓ ability of apoB in LDL to bind to LDLR)
and autosomal dominant hyperchol. type 3 (gain-of-fxn mutations in PCSK9 → ↓ recycling of LDLR to
hepatocyte surface) have similar phenotypes. LDL-C > 190 mg/dL should prompt consideration of genetic
etiology.

Polygenic FH: multiple small effect genetic variants without one causal gene (1:7)
 Familial combined hyperlipidemia (1:200): polygenic; ↑ LDL-C, ↑ TG, ↓ HDL-C; ↑ CAD

Familial hypertriglyceridemia (FHTG, 1:500): polygenic; ↑ TG, ↓ HDL-C; ↑ pancreatitis

Physical exam findings

Tendon xanthomas: seen on Achilles, elbows, and hands; implies high LDL-C

Eruptive xanthomas: pimple-like lesions on extensor surfaces; implies TG >1000 mg/dL

Xanthelasma: yellowish streaks on eyelids seen in various dyslipidemias

Corneal arcus: common in older adults; implies hyperlipidemia in young Pts

Secondary Dyslipidemias

Category Disorders

Endocrinopathies Type 2 diabetes (↑ TG, ↓ HDL-C); lipodystrophy (↑ TG)

Hypothyroidism (↑ LDL-C, ↑ TG); hyperthyroidism (↓ LDL-C)
Cushing’s syndrome & exogenous steroids (↑ LDL-C, ↑ TG)

Renal diseases Renal failure (↑ LDL-C, ↑ TG); nephrotic syndrome (↑ LDL-C, ↑ TG)

Hepatic diseases Cholestasis, PBC (↑ LDL-C); liver failure (↓ LDL-C); acute hepatitis (↑ TG)

Lifestyle Obesity, sat & trans-fat (↑ TG, ↓ HDL-C, ↑ LDL-C); sedentary lifestyle (↓ HDL-
C); alcohol (↑ TG, ↑ HDL-C); tobacco (↓ HDL-C); anorexia (↑ LDL-C); very-low-
fat + high-refined-carb diet (↑ TG); pregnancy (↑ LDL-C; ↑ TG)

Medications Thiazides (↑ LDL-C, ↑ TG); βB (except carvedilol, ↑ TG, ↓ HDL-C); estrogens (↑

TG, ↑ HDL-C); androgens (↓ HDL-C); cyclosporine, amiodarone (↑ LDL-C);
propofol, bile acid sequestrants, protease inhibitor, retinoic acid, sirolimus,
raloxifene, tamoxifen (↑ TG)

Treatment of LDL-C (Lancet 2014;384:607 & Eur Heart J 2020;41:111)

Every 1 mmol (˜39 mg/dL) ↓ LDL-C → 22% ↓ major vascular events in individuals w/ & w/o CAD in data from
statin trials (Lancet 2010;376:1670)

Similar clinical benefit also seen w/ nonstatin Rxs that upregulate LDLR when taking into account magnitude
and duration of LDL-C lowering (JAMA 2016;316:1289 & EHJ 2018;39:2540)

Consistent CV benefit even when starting w/ LDL-C <70 mg/dL (JAMA Cardiol 2018;3:823)

No evidence to suggest harm from very low LDL-C levels <20 mg/dL (Lancet 2017;390:1962)

Therapeutic lifestyle modification: avoidance of trans-fat, saturated fat; increased dietary fiber, reduced
dietary cholesterol (animal products), plant-based diets, reduced body weight, daily exercise

Statins

↓ cholesterol synthesis by HMG Co-A reductase inhibition → ↑ hepatic LDLR activity

↓ LDL-C by 20-60%, ↓ TG by 10-40%

myalgias in ˜10%, but ˜90% of these appear to be nocebo effect (NEJM 2020;383:2182)

myopathy (ie, myalgias + ↑ CK) <0.1% & rhabdomyolysis <0.01%, both dose dependent (ATVB 2019;39:e38)

↑ ALT in ˜1% (dose dependent); hepatotoxicity ˜0.001%; [check mark] ALT before starting and then after as
clinically indicated

↑ risk of DM, typically preexisting pre-DM → DM (JAMA 2015;313:1029); screen if risk factors

↓ MACE in secondary & primary prevention populations (Lancet 2016;388:2532)

Statin Doses & LDL-C Reduction

Intensity ↓ Rosuva Atorva Simva Prava Lova Fluva Pitava

LDL-
C

High ≥50% 20-40 40-80 (80)

Mod 30- 5-10 10-20 20-40 40-80 40 80 2-4

50%

Low <30% 10 10-20 20 20-40 1

Doses are in mg. Doubling of statin dose ↓ LDL-C by ˜6%. Simva 80 mg has ↑ myopathy risk and should
not be used unless dose already tolerated >12 mos.

P.26
Ezetimibe

blocks GI cholesterol uptake via NPC1L1 receptor in intestinal brush border

↓ LDL-C by 24%

well tolerated with no clear side effects

↓ MACE when added to statin post-ACS (IMPROVE-IT, NEJM 2015;372:2387)

PCSK9 inhibitors

prevent PCSK9 from binding to LDLR, allowing ↑ recycling of LDLR to surface of hepatocyte and ↑ LDL
clearance; monoclonal Ab (evolocumab & alirocumab) bind to PCSK9 and siRNA (inclisiran) prevents PCSK9
synthesis

↓ LDL-C by 50% (inclisiran) to ˜68% (time-averaged for mAb), ↓ TG by ˜20% mAb SC dosing q2 or 4 wks; well
tolerated w/ occasional mild injection site reactions

↓ MACE with mAb (NEJM 2017;376:1713 & 2018;379:2097); CV outcomes trial for inclisiran ongoing (NEJM
2020;382:1507)

Bempedoic acid

↓ ATP citrate lyase (upstream to HMG Co-A reductase); specific isoenzyme that converts bempedoic acid to
active metabolite not present in skeletal muscle
 ↓ LDL-C by ˜16% (NEJM 2019;380:1022)

↑ risk of muscle spasms, elevated aminotransferases, hyperuricemia/gout, ↓ eGFR, and tendon rupture

CV outcomes trial ongoing

Bile acid sequestrants: prevent reabsorption of bile acids in ileum → ↑ hepatic LDLR activity; ↓ LDL-C by ˜20%;
poorly tolerated due to GI distress

Lomitapide: MTP inhibitor ↓ hepatic VLDL synthesis; ↑ hepatic fat & liver side effects; used for homozygous FH

ANGPTL3 inhibitors

ANGPTL3 inhibits lipoprotein lipase & endothelial lipase; inhibiting it derepresses those enzymes → ↑ VLDL
clearance; monoclonal Ab (evinacumab) approved for HoFH; antisense oligonucleotide under study

↓ LDL-C by up to ˜50% (even in HoFH) & TG by ˜60% (NEJM 2020;383:711 & 2307)

Treatment of hypertriglyceridemia (Lancet 2014;384:626)

Reasonable to treat very high levels (>500-1000 mg/dL) to ↓ risk of pancreatitis

High levels of TG associated with ↑ risk of MI, likely reflecting atherogenic VLDL particles (which is ignored
when one only considers LDL-C)

In RCTs, TG lowering associated w/↓ MACE independent of LDL-C (Circ 2019;140:1308)

Lifestyle modification including wt loss, diet (low fat, avoid refined carbs & alcohol), control of DM, and
review of meds that might be contributing should be initial therapy

Statin (up to ˜40% ↓ TG) if Pt also has at least intermediate ASCVD risk (≥7.5%)

Fibrates (gemfibrozil & fenofibrate): ↓ TG by ˜50%, ↓ LDL-C by <20%. Mixed data in terms of ↓ vascular events,
? greater benefit if high TG (Circ 1992;85:37; NEJM 1999;341:410; Lancet 2005;366:1849; NEJM
2010;362:1563).

Omega-3 fatty acids

Dietary supplements without clear benefit (NEJM 2018; 379:1540)

Pharmacologic high doses (2-4 g/d) of purified EPA and/or DHA ↓ TG by up to ˜45% in Pts w/ high TG levels

Icosapent ethyl (purified ethyl ester EPA) 4 g/d in Pts w/ CVD or high-risk DM w/ TG 135-499 mg/dL → 25% ↓
MACE and 20% ↓ CV death; ↑ AF & ? ↑ bleeding (REDUCE-IT, NEJM 2019;380:11)

No CV benefit (HR 0.99) of 2 g/d EPA (carboxylic acid formulation) + 2 g/d DHA (STRENGTH, JAMA
2020;324:2268)

Reason(s) for difference seen between trials remains debated. Similar ↓ TG (˜20%) and benefit in STRENGTH
exceeded what would be expected from TG ↓ alone (Circ 2019;140:1308). Difference may be due to
formulation (but levels of EPA achieved in STRENGTH ˜2/3 of that in REDUCE-IT) or concomitant DHA negating
benefit of EPA. REDUCE-IT used mineral oil placebo that resulted in 30% ↑ CRP, whereas STRENGTH used corn
oil placebo with no effect on CRP.

ANGPTL3 inhibitors (vide supra) & ApoC3 inhibitors (ApoC3 inhibits lipoprotein lipase; inhibiting it derepresses
that enzyme → ↑ VLDL clearance) under study and ↓ TG in Pts w/ hypertriglyceridemia by ˜70-80% (NEJM
2015;373:438; Circ 2019;140:470)

Treatment of lipoprotein(a)
Low-density lipoprotein with apoB bound to apolipoprotein(a), a protein with homology to plasminogen (but
inactive)

Levels are primarily genetically determined; marked racial/ethnic variability

Mendelian randomization studies suggest causal role in CAD and aortic stenosis (NEJM 2009;361:2518);
pathobiology may be related to proatherogenic (cholesterol-rich LDL particle), pro-inflam. (oxidized
 phospholipids), and procoagulant (plasminogen) properties

P.27
Reasonable to [check mark] once if FHx CAD or in adulthood for risk stratification; endorsed as risk-enhancer
in lipid guidelines. >50 mg/dL (˜80th %ile) associated with ↑ CV risk.

Treatment of Lp(a) itself remains controversial

Statins do not ↓ Lp(a)

Niacin ↓ Lp(a) by ˜30%, but did not ↓ CV events in Pts not selected for high Lp(a)

PCSK9i ↓ 25-30% (Circ 2019;139:1483); also ↓ w/ lomitapide, apheresis

Trials of RNA interference therapies that ↓↓ Lp(a) ongoing (NEJM 2020;382:244)

Treatment of HDL-C (Lancet 2014;384:618)

Low HDL-C associated with ↑ risk of MI

However, Mendelian randomization studies do not support causal role (Lancet 2012;380:572) no longer a
focus of management

Niacin: in Pts w/ well-controlled LDL-C (<80 mg/dL) on a statin, minimally ↓ LDL, modestly ↑ HDL-C, and did
not ↓ CV events (NEJM 2011;365:2255 & 2014;371:203)

CETP inhibitors: prevent transfer of cholesterol from HDL particles to LDL & VLDL particles, thereby ↑ HDL-C
levels (but not necessarily facilitating reverse cholesterol transport). CETPi that solely ↑ HDL-C did not lead to
clinical benefit in Pts w/ wellcontrolled LDL-C on a statin (NEJM 2012;367:2089); another that ↑ HDL-C by 140%
and ↓ LDL-C by ˜30%, ↓ MACE by 9% but likely driven by LDL-C reduction (NEJM 2017;377:1217).

Continues to be of interest to find drugs that facilitate reverse cholesterol transport, which is better
correlated with CV risk than HDL-C (NEJM 2014;371:2383)

Society guidelines

2018 ACC/AHA Cholesterol Guidelines (Circ 2018;10.1161)

Population Recommendation

Very-high-risk ASCVD* High-intensity statin; add EZE then PCSK9i if

LDL-C ≥70

Clinical ASCVD High-intensity statin (? mod if >75 y), add EZE

if LDL-C ≥70

LDL-C ≥190 mg/dL High-intensity statin; add EZE or PCKS9i if

LDL-C ≥100

DM, age 40-75 y High-intensity statin (? moderate if no CV RFs)

Age 40-75 y (and none of above); ≥20% High-intensity statin

calc 10-y risk
 7.5%- Moderate-intensity statin; if uncertain
<20% consider CAC

5-<7.5% Moderate-intensity statin reasonable

<5% Emphasize lifestyle

Clinical atherosclerotic CV disease (ASCVD) includes h/o ACS, stable angina, arterial revascularization, stroke,
TIA, or PAD presumed to be of atherosclerotic origin. Very high risk defined as multiple major ASCVD events
(MI, stroke, sx PAD) or 1 major event + multiple high-risk conditions (age ≥65 y, DM, HTN, CKD, smoking, FH,
prior PCI/CABG).

10-y CV risk score for CHD or stroke based on age, sex, race, SBP, TC, LDL-C, DM, tobacco use, BP Rx;
http://my.americanheart.org/cvriskcalculator

Additional risk factors to consider include: LDL-C ≥160 mg/dL, genetic hyperlipidemia, FHx premature ASCVD
(M <50 y, F <55 y), hsCRP >2 mg/L, CAC score ≥300 or ≥75th %ile, ABI <0.9, Lp(a) ≥50 mg/dL or ≥125 nmol/L

If Pt does not tolerate high-intensity statin, consider dose ↓ or Δ statin (most commonly atorva to rosuva due
to different metabolism) before discontinuation of statin

2019 ESC/EAS Dyslipidemia Guidelines (EHJ 2020;41:111)

CV Risk Characteristics LDL-C Target (mg/dL)a

ASCVD (clinical or unequivocal on imaging)

DM + target organ damageb
<55 (<40 if recurrent vascular
Very high eGFR <30
events)
SCORE ≥10% 10-y risk of fatal CV disease
FH w/ ASCVD or major risk factor

LDL-C >190 mg/dL or SBP ≥180/110

DM w/o target organ damage but ≥10 y
High duration eGFR 30-59 <70
SCORE 5-<10% 10-y risk of fatal CV disease
FH w/o ASCVD or major risk factor

DM <10 y duration
Moderate <100
SCORE 1-<5% 10-y risk of fatal CV disease

Low SCORE <1% 10-y risk of fatal CV disease <116

a
Target is ≥50% reduction in LDL-C plus achieving target level.

b
Microalbuminuria, retinopathy, or neuropathy.
 Start with high-intensity statin, then add EZE and then PCSK9i to achieve goal

P.28

CV RISK REDUCTION IN DIABETES

Definition of diabetes mellitus (Diabetes Care 2021;44:S15)

Either HbA1c ≥6.5%, fasting glc ≥126 mg/dL, or glucose ≥200 mg/dL 2h after OGTT × 2 (for any test) or single

random glc ≥200 mg/dL w/ classic sx of hyperglycemia; all tests equally reasonable (nb, may be on one
test but not another); OGTT preferred in pregnancy

Prediabetes: glc higher than normal, but not frank DM; >1/3 of U.S. population HbA1c 5.7-6.4%, impaired
fasting glc (IFG) 100-125 mg/dL, or 2 h prandial glc 140-199 mg/dL Preventing progression to DM: diet &
exercise (58% ↓), metformin (31% ↓; NEJM 2002;346:393), TZD (60% ↓; Lancet 2006;368:1096)

Glycemic treatment goals (Diabetes Care 2021;44:S73)

[check mark] HbA1c q3-6mo, goal <7% for most Pts

Goal <6.5% if low risk of hypoglycemia

Goal ≤8% if h/o severe hypoglycemia, elderly, or other comorbidity

Microvascular complications (nephropathy, retinopathy, neuropathy) ↓↓ by strict glycemic control (NEJM

1993;329:977)

Effect of strict glycemic control on macrovascular complications (ASCVD) more nuanced. Benefit in T1D (NEJM
2005;353:2643) & T2D, but emerged after a decade (NEJM 2015;372:2197). In shorter-term trials (˜5 yrs),
modest ↓ in risk of MI, but no effect on death and even ↑ in some studies, potentially because of hypoglycemia
(Lancet 2009;373:1765).

Some classes of glucose-lowering agents have been shown to ↓ CV complications (vide infra), causing paradigm
shift to tailor pharmacotherapy based on ↓ CV risk

Select Glucose-Lowering Agents

Medication ↓ HbA1c Comments

(%)

Metformin ˜1-1.5 ↓ hepatic gluconeogenesis. Mild wt ↓. 1st line for T2D. Rare
lactic acidosis. Caution if GFR 30-45; contraindicated if
<30. Possible CV benefit.

SGLT2 inhibitors ˜0.5-1.0 ↑ glucosuria. Wt ↓. Genital mycotic infxn. ↓ CVD/HHF, ↓

progression of renal disease,? ↓ MI if ASCVD.

GLP1 RAs ˜1-1.5 ↑ glc-depend insulin secretion. Wt ↓↓, N/V. ↓

CVD/MI/stroke, espec. if ASCVD; ↓ prog of albuminuria.

DPP-4 inhibitors ˜0.5-1.0 Block degradation GLP1 & GIP → ↑ insulin ↑ risk of HF seen
w/ saxagliptin, not w/ others
 Sulfonylureas (SU) ˜1.5% ↑ insulin secretion. Hypoglycemia; wt gain.

Thiazolidinediones ˜1% ↑ insulin sensitivity in adipose & muscle. Wt ↑, fluid

(TZD) retention & CHF. Hepatotoxicity. ↑ MI w/ rosiglitazone?
Contraindicated in HF & liver dysfxn.

Insulin Variable Hypoglycemia; wt gain. Mandatory in T1D; consider in T2D

if oral Rx inadequate.

(Diabetes Care 2021;44:S111)

Insulin Preparations (Diabetes Care 2019;44:S111)

Type (example) Onset Peak Duration Comments

Rapid (lispro, aspart) Immed 1-2 h <4 h Give immediately before meal

Short (regular) ˜30 min 2-3 h 5-8 h Give ˜30 min before meal

Intermed. (NPH) 2-3 h 4-8 h 10-14 h Can cause protamine Ab prod

Long (glargine, detemir) 1-2 h n/a 12-24 h Once-daily basal insulin

Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i)

Mechanism of action: inhibit SGLT2 in proximal convoluted tubule, resulting in impaired reuptake of glucose by
the nephron and glucose wasting in the urine

Concomitant ↑ delivery of Na to distal convoluted tubule sensed by macula densa → tubuloglomerular

feedback → afferent arteriole vasoconstriction. ↑ NaCl sensed by macula densa also → inhibition of renin
release → efferent arteriole vasodilation. Combination → ↓ intraglomerular pressure

Other favorable off-target effects are postulated but unproven

Clinical effects: ↓ serum glucose & HbA1c, ↓ BP (via ? diuretic and inhibition of RAAS axis), weight loss

In general DM Pts: ↓ hospitalization for HF by ˜30%; variable effect on CV death (none to ↓ 38%), ↓ MI by ˜10-
15% in Pts w/ established ASCVD; ↓ progression of kidney disease by ˜45% (Lancet 2019;393:31)

P.29
In Pts w/ HF (both rEF & pEF): ↓ CV death or hospitalization for HF by 20-25%, irrespective of DM (DAPA-HF,
NEJM 2019;381:1995; EMPEROR-Reduced, NEJM 2000;383:1413; EMPEROR-Preserved, NEJM 2021;385:1451)

In Pts w/ CKD + albuminuria: ↓ progression of kidney disease by 30-40%, CVD/HF by ˜30%, MACE by 10-15% and
all-cause mortality by 20-25%, again irrespective of DM (CREDENCE, NEJM 2019;380:2295; DAPA-CKD, NEJM
2020;383:1436)
 Complications: mycotic genital infections; euglycemic DKA; ? increase in lower extremity amputation (seen
only with canagliflozin and only in 1 trial)

Initial small drop in eGFR (<5 mL/min/1.73 m2) but no ↑ acute kidney injury (and long-term benefit as noted
above); not recommended to initiate if eGFR <25

Glucagon-Like Peptide 1 Receptor Agonists (GLP1-RA)

Mechanism of action: ↑ prandial release of endogenous insulin, delays gastric emptying, suppresses glucagon
release, and ↑ insulin sensitivity

Clinical effects: ↓ serum glucose & HbA1c, reduced albuminuria, slight ↓ BP, weight loss

In DM: 12% ↓ in MACE (perhaps mostly in Pts w/ ASCVD), 9% ↓ HF hospitalization, 17% ↓ in progression of kidney
disease, due largely to ↓ albuminuria (Lancet Diab & Endo 2019;7:776)

Most GLP1-RA are SC weekly; oral semaglutide also available

Complications: GI side effects, ? pancreatitis

Treatment Algorithm to Reduce CV Risk (EHJ 2020;41:255; Diabetes Care 2021;44:S111)

U.S. guidelines start with metformin; European guidelines note that if drug naïve and high risk, can
start with one of the drugs below

w/ Heart Failure w/ CKD + Albuminuria w/ or at High Risk for ASCVD

SGLT2i SGLT2i GLP1-RA or SGLT2i

If A1c above target, then add the other class (GLP1-RA or SGLT2i).
If A1c still above target, add additional drugs based on side-effect profile.

Management of hyperglycemia (not DKA) in inpatients (Clin Ther

2013;35:724)
Identify reversible causes/exacerbators (dextrose IVF, glucocorticoids, post-op, ↑ carb diet)

Treatment goals: avoid hypoglycemia, extreme hyperglycemia (>180 mg/dL)

Transition to inpatient

T1D: do not stop basal insulin (can lead to DKA)

T2D: stopping oral DM meds generally preferred to avoid hypoglycemia or med interaction (except if short stay,
excellent outpatient control, no plan for IV contrast, normal diet). If Pt w/ known insulin needs do not rely on
sliding scale alone (Diabetes Care 2018;41:S144).

Starting new insulin regimen

Basal = 0.2-0.4 u/kg/d NPH Q12h or detemir or glargine

+ correction insulin for BG >150 mg/dL

+ prandial insulin if eating: 0.05-0.1 u/kg/meal lispro, aspart, or regular

 When NPO

T1D: continue basal insulin at current dose or 75% depending on BG control

T2D: continue basal insulin at 25-75% depending on BG control and level of insulin resistance. Hold all prandial
insulin.

Discharge regimen: similar to admission regimen unless poor outpatient control or strong reason for Δ. Arrange
early insulin and glucometer teaching, prompt outpatient follow-up.

Risk factor management and treatment goals (Diabetes Care

2021;44:S125)
Weight loss (dietary/drugs/surgery) can regress or resolve DM (Endo Rev 2018;39:79; NEJM 2018;379:1107).
Consider bariatric surgery if BMI >35 (or >30 if uncontrolled DM): ↓ BMI, HbA1c, triglycerides, insulin use, MACE,
all-cause mortality (STAMPEDE, NEJM 2017;376:641; JAMA 2019;322:1271).

BP ≤130/80 if high CV risk (if not in all), otherwise ≤140/90 if lower risk; benefit of ACEI/ARB (especially if
albuminuria)

Lipids: statin in all (high intensity if ASCVD); if ASCVD and LDL-C ≥70 mg/dL despite max-tolerated statin,
consider adding EZE and then PCSK9 inhibitor (see “Dyslipidemia”)

Antiplatelet therapy (Diabetes Care 2021;44:S125)

If ASCVD: ASA. Addition of ticagrelor reasonable if Pts at high risk of ischemic events (prior MI or PCI) and low
risk of bleeding as shown to ↓ MACE and ↑ bleeding, but not fatal bleeds or ICH (JACC 2016;67:2732; THEMIS-
PCI, Lancet 2019;394:1169). May then consider step down to P2Y12 monotherapy.

In 1° prevention ASA reasonable in Pts at high ischemic risk and low bleeding risk; over ˜7 yrs, ˜1% absolute ↓
in MACE and ˜1% absolute ↑ in major bleed (ASCEND, NEJM 2018;379:1529)