Primary Prevention of Cardiovascular Disease

and Public Health

Carol Heunisch, Pharm.D., BCPS, BCCP

Director, Drug Policy and Education, North Region
Endeavor Health
Highland Park, IL

Conflict of Interest Disclosure

I have no conflicts of interest to disclose.

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 Learning Objectives
Identify pharmacotherapeutic agents that reduce the risk of developing cardiovascular disease
(CVD).
Develop a treatment plan that incorporates lifestyle modifications and evidence-based
pharmacotherapy to reduce the risk of an index cardiovascular event for a given patient scenario.
Develop a tobacco cessation treatment plan for a patient who requests assistance for a quit
attempt.
Evaluate a given patient scenario to determine CVD risk and recommend appropriate lipid
therapy.
Determine appropriate patients to recommend initiation of aspirin therapy for the primary
prevention of CVD.
Counsel a patient on appropriate complementary and alternative pharmacotherapeutic agents to
optimize CVD risk reduction, including omega-3 fatty acids.

Agenda

Risk Lifestyle Tobacco

Lipid therapy
assessment interventions Cessation

Obesity
SGLT2i in Omega-3
(GLP-1 RA & Aspirin
GLP-1 RA/GIP)
HF and CKD fatty acids

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 Presentation Structure

Review of key Deep dive on

concepts newer data

Cardiovascular Risk Assessment Tools

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 Key Risk Factors for Developing CVD
Modifiable Risk Factors Nonmodifiable Risk Factors
Tobacco exposure Age (male ≥45 years, female ≥55 years)
Dietary intake Gender
Premature CVD in first degree relative
Physical inactivity (<55 years in male relative; <65 years in female
relative)
Blood pressure Ethnicity
Blood glucose elevation
Abnormal cholesterol values
Obesity
Cocaine/amphetamine use, Alcohol use

Risk Calculators Limitations

• CV risk may be underestimated (in general):
– Those with previous CV event
– Evidence of LVH or hypertensive retinopathy
– Familial hypercholesterolemia or LDL ≥190 mg/dL at baseline
– Elevated BP
– Diabetes
– Renal dysfunction

• Assess traditional ASCVD risk factors in adults ages 20-39 years every 4-6 years

• Routinely assess traditional CV risk factors and calculate ASCVD score in adults
ages 40-75 years

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 Commonly Used Risk Calculators in Primary Prevention
Risk Assessment Tool Guidelines Referencing Ages Useful For Outcomes Assessed
10-year and lifetime risk of MI
PCE ACC/AHA, ADA, USPSTF 40-79 years
or stroke (fatal, nonfatal)
UK National Institute of
QRISK3 25-84 years 10-year risk of MI or stroke
Health and Care Excellence
Framingham Score NLA (2014), ATP III 30-79 years 10-year risk of MI or death
≥45 years (women) 10-30-year risk of MI, stroke,
Reynolds Risk Score None
50-79 years (men) or revascularization
10-year ASCVD risk and
Million Hearts None 40-79 years
projects change with therapy

All risk calculators have inherent limitations and should be used in conjunction with clinical assessment and patient-
centered discussions regarding the potential risks and benefits of any therapy being considered

ACC/AHA Pooled Cohort Equations (PCE)

May under-estimate risk in
• Chronic inflammatory conditions (e.g., HIV)
• Those at socioeconomic disadvantage

May over-estimate risk in

• Those at higher socioeconomic status
• Those with continued access to preventative services

Less well-calibrated in
• More modern populations compared to the older cohorts from which it was derived
• Consider risk-enhancing factors for those at borderline or intermediate risk
• While PCE is generally recommended, may consider alternative tool if that tool is validated in a
similar population to an individual being assessed
J Am Coll Cardiol 2019;74:e177-232

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 Predicting Risk of Cardiovascular Disease Events
(PREVENT)
• Introduced by AHA in November 2023 to address gaps with PCE and other risk
assessment tools
• Allows for estimates of both short-term and long-term risk among adults 30 to 79
years of age
• Incorporates cardiovascular-kidney-metabolic health variables
– Chronic kidney disease (eGFR)
– Diabetes (hemoglobin A1c and urine albumin-to-creatinine ratio)
• Removes race from the equation
• Adds considerations of social determinants of health through use of the social
deprivation index

Circulation 2023; 148: 1982-2004

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Predicting Risk of Cardiovascular Disease Events

(PREVENT)
• Online calculator made available in January 2024:
– https://professional.heart.org/en/guidelines-and-statements/prevent-calculator

• PCE is still endorsed by current guidelines as the calculator tool of choice.

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 Risk Enhancers: 2018 ACC/AHA Cholesterol Guidelines
Risk-Enhancing Factors for Clinician-Patient Discussion Diabetes-Specific Independent Risk Enhancers
• Family history of premature ASCVD (men <55, female <65) • Long duration of diabetes (≥ 10 years T2DM,
• Primary hypercholesterolemia (LDL 160-189 mg/dL) ≥20 years T1DM)
• Metabolic syndrome • Albuminuria (≥30 mcg of albumin/mg
creatinine)
• Chronic kidney disease (eGFR 15-59 mL/min/1.73 m2)
• Nephropathy (eGFR <60 mL/min/1.73 m2)
• Chronic inflammatory conditions (RA, HIV, psoriasis)
• Retinopathy
• High-risk race/ethnicities (e.g., South Asian ancestry)
• Neuropathy
• Triglycerides ≥175 mg/dL (persistently)
• ABI <0.9
• Elevated biomarkers, if measured (CRP, Lp(a), apoB, ABI <0.9)
• Premature menopause or pregnancy-associated conditions
that increase later ASCVD risk (e.g., preeclampsia)

J Am Coll Cardiol. 2019;73(24):e285-e350.

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Lifestyle Interventions

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 Lifestyle Intervention: Diet
2019 ACC/AHA Primary Prevention 2020 USPSTF Guidelines
Promoting a healthy lifestyle throughout life is the most important way
to prevent ASCVD, HF and atrial fibrillation Increase fruits, vegetables, whole grains, fish and
Recommend diet high in vegetables, fruits, legumes, nuts, whole other healthy fats
grains, fish and lean vegetable or animal protein to reduce ASCVD risk
Avoid trans fats
Reduce saturated fats, sodium, sweets, added
Replacing saturated fats with monounsaturated and polyunsaturated sugar
fats can help reduce ASCVD risk
A diet low in cholesterol and sodium helps reduce ASCVD risk
Minimize consumption of processed meats, refined carbohydrates and Promote DASH and Mediterranean diet
sweetened beverages to reduce ASCVD risk
Potential barriers to attaining a heart healthy diet should be assessed Behavioral change approach includes setting
and considered including food access and economic factors that affect goals, active self-monitoring, addressing barriers,
patient adherence and motivational interviewing

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Lifestyle Intervention: Potassium

• Associated with reduced rates of hypertension and stroke

• Intake of 1380 mg potassium chloride:

– Reduces SBP by 2 mm Hg in normotensive patients
– Reduces SBP by 4-5 mm Hg for hypertensives
– Greater effects in blacks and high sodium intake
– May be mediated by sodium / potassium intake changes.

• Goal intake: 3500 mg – 4700 mg daily

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 Lifestyle Intervention: Alcohol
• One alcoholic drink = 14 grams pure alcohol
– About 12 ounces of beer, 5 ounces of wine, or 1.5 ounces liquor
– Up to 1 drink per day for women (if any)
– Up to 2 drinks per day for men (if any)

• Alcohol increases risk of hypertension, atrial fibrillation, heart

failure, obstructive sleep apnea, obesity, and metabolic
syndrome

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Impact of Lifestyle Modifications on SBP

SBP effect in hypertensive SBP effect in normotensive
Modification
patients patients
Weight reduction -5 mm Hg -2/3 mm Hg
Adopt DASH diet -11 mg Hg -3 mm Hg
Reduce sodium intake -5/6 mm Hg -2/3 mm Hg
Increase potassium intake -4/5 mm Hg -2 mm Hg
Physical activity -5/8 mm Hg -2/4 mm Hg

Moderate alcohol consumption -4 mm Hg -3 mm Hg

Potential total effect on SBP -34 mm Hg SBP -14 mm Hg SBP

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 Self Assessment Question # 1:
A 38-year-old woman (BMI 24 kg/m2) asks how much she should exercise. She
currently has a desk job and has "not exercised in years." Her father recently had
an MI, so she is motivated to begin exercising. Her medical history is non-
contributory. Her ASCVD score using the PCE is less than 1%. What is the best
recommendation for this patient?

a. No changes are currently needed because her ASCVD score is low

b. No changes are currently needed because she is younger than 40
c. Recommend 150 minutes of moderate activity per week or 75 minutes of
vigorous-activity per week
d. Recommend 150 minutes of moderate-activity per week only if she begins to
gain weight
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Self Assessment Question # 1:

A 38-year-old woman (BMI 24 kg/m2) asks how much she should exercise. She
currently has a desk job and has "not exercised in years." Her father recently had
an MI, so she is motivated to begin exercising. Her medical history is non-
contributory. Her ASCVD score using the PCE is less than 1%. What is the best
recommendation for this patient?

a. No changes are currently needed because her ASCVD score is low

b. No changes are currently needed because she is younger than 40
c. Recommend 150 minutes of moderate activity per week or 75 minutes of
vigorous-activity per week
d. Recommend 150 minutes of moderate-activity per week only if she begins to
gain weight
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 Lipid Therapy

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• Lifestyle interventions should be emphasized

• Who should get a statin?
o Age 0-19 years with familial hypercholesterolemia
o Ages 20-39 with positive family history of premature ASCVD and LDL-C ≥160
mg/dL
o LDL-C ≥ 190 mg/dL→high-intensity statin
o Age 40-75 years AND diabetes→moderate intensity sta n
 Risk assessment to consider high-intensity statin

Circulation 2019.139;e1082-1143

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 • For those ages 40-75 years, with LDL-C ≥70 <190 mg/dL and WITHOUT
diabetes, use 10-year ASCVD risk to begin discussion:
o Low risk (<5%): emphasize lifestyle modifications to reduce risk
o Borderline risk (5%- <7.5%): IF risk enhancers present, consider
moderate-intensity statin
o High risk (≥ 20%): initiate statin to reduce LDL-C ≥ 50%
• For those over the age of 75, a clinical assessment and risk discussion
should take place

Circulation 2019.139;e1082-1143

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• For those ages 40-75 years, with LDL-C ≥70 <190 mg/dL and WITHOUT diabetes,
use 10-year ASCVD risk to begin discussion:
o Intermediate risk ( ≥ 7.5%- <20%): if based on risk estimate AND risk enhancers,
statin therapy is favored, initiate a moderate-intensity statin to reduce LDL-C by
30%-49%
 If risk decision is uncertain, consider measuring coronary artery calcium (CAC) in selected
adults:
 CAC = zero, consider statin only if diabetes, cigarette smoking or premature CHD family
history
 CAC 1-99: statin is favored, especially at age over 55
 CAC 100+ and/or 75th percentile: initiate statin therapy

Circulation 2019.139;e1082-1143

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 Self-assessment question # 2
A 48-year-old man with a medical history of HTN (blood pressure 125/78)
taking ramipril 5 mg daily is being considered for statin therapy. His
current lipid panel includes total cholesterol 180 mg/dL, HDL 40 mg/dL,
and LDL 125 mg/dL. His calculated ASCVD score using PCE is 6.8%. He has
no other risk factors. Which is the best recommendation for this patient
regarding statin therapy?
A. Initiate atorvastatin 10 mg daily
B. Initiate rosuvastatin 20 mg daily
C. Initiate pravastatin 40 mg daily
D. Statin therapy is currently not indicated.

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Self-assessment question # 2
A 48-year-old man with a medical history of HTN (blood pressure 125/78)
taking Ramipril 5 mg daily is being considered for statin therapy. His
current lipid panel includes total cholesterol 180 mg/dL, HDL 40 mg/dL,
and LDL 125 mg/dL. His calculated ASCVD score using PCE is 6.8%. He has
no other risk factors. Which is the best recommendation for this patient
regarding statin therapy?
A. Initiate atorvastatin 10 mg daily
B. Initiate rosuvastatin 20 mg daily
C. Initiate pravastatin 40 mg daily
D. Statin therapy is currently not indicated.

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 Tobacco Cessation

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Guideline Recommendations
2019 ACC/AHA Primary Prevention
• All adults should be assessed at each interaction for tobacco use.
• Patient status for tobacco use should be recorded as a vital sign to facilitate tobacco cessation efforts.
• All adults who use tobacco should be strongly advised to quit.
• Behavioral intervention plus pharmacotherapy combination is recommended for greatest quit rate success.
• All persons should avoid secondhand smoke exposure to reduce ASCVD risk.

2021 USPSTF
• Recommend pharmacotherapy and behavioral interventions for tobacco cessation for all non-pregnant adults
• Recommend behavioral interventions for pregnant adults. Insufficient data to recommend pharmacotherapy
interventions in pregnant adults
• Insufficient evidence to recommend electronic nicotine delivery systems for smoking cessation
• Recommends tobacco cessation interventions with proven effectiveness and established safety
• Promotes 5 A's: Ask about tobacco, Advise to quit, Assess willingness, Assist in quit attempt, Arrange follow-up

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 Pharmacotherapy Options
Bupropion Sustained Release Varenicline
Class Aminoketone antidepressant Partial nicotine agonist
150 mg daily x3 days, then 150 mg twice daily for 0.5 mg daily x3 days, then 0.5 mg twice daily for
7-14 days prior to quit date 4 days, then 1 mg twice daily for 2-24 weeks
Dosing
Continue for 7-12 weeks; up to 6 months in some Start up to 5 weeks prior to quit date
Insomnia, abnormal dreams, suicidal ideation,
Key ADE Insomnia, dry mouth, dizziness
nausea/vomiting
Contraindicated: seizures, eating disorders, abrupt Black box warning for neuropsychiatric events
Other
discontinuation of alcohol or sedatives, MAOI removed in 2016

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Select Nicotine Replacement Products

Nicotine Patch Nicotine Gum Nicotine Lozenge
Dosing Factor Number cigarettes per day Time of first cigarette after waking up
≥10 cigarettes/day: 21 mg/d ≤30 min: 4 mg
Dose
<10 cigarettes/day: 14 mg/d >30 min: 2 mg
21 mg/d x28-42 days, then 14 mg/d x14
Weeks 1-6: 1 piece every 1-2 hours
days, then 7 mg/d x14 days
Tapering Weeks 7-9: 1 piece every 2-4 hours
Weeks 10-12: 1 piece every 4-8 hours
14 mg/d x42 days, then 7 mg/d x14 days
Maximum 24
Rotate site daily; pieces/day Maximum 20 lozenges/day

Wear for 16 hours per day; “Chew and park” Dissolves slowly over 10-30
Other
minutes
Evening use may increase sleep Avoid food/drink
disturbance for 8-10 weeks within 15 minutes Use for up 12 weeks
before/after

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 Comparing Strategies: EAGLES Trial
Design
• Randomized 1:1:1:1 varenicline vs bupropion vs nicotine patch vs. placebo for 12-weeks (double-blind, triple-dummy)
• N=8144 randomized (n=4116 with psychiatric disorders, n=4028 without)

Primary Outcomes Assessed

• Efficacy: Biochemically confirmed abstinence at weeks 9-12
• Safety: moderate and severe neuropsychiatric events

Key Results
• Varenicline higher abstinence vs. bupropion (OR 1.75; 95% CI 1.52-2.01)
• Varenicline higher abstinence vs. nicotine patch (OR 1.68; 95% CI 1.46-1.93)
• Varenicline (OR 3.61; 95% CI 3.07-4.24), bupropion (OR 2.07; 95% CI 1.75-2.45) and nicotine patch (OR 2.15; 95% CI
1.82-2.54) more effective than placebo
• Neuropsychiatric adverse events similar with either varenicline or bupropion vs. nicotine patch or placebo
Lancet 2016; 387:2507-20

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Self Assessment Question #3:

A 68-year-old female patient has a 40 pack-year history and currently smokes 20
cigarettes daily with the first cigarette within 10 minutes of waking daily. She has a
medical history of anxiety and is working to taper and discontinue clonazepam 0.5
mg twice daily for generalized anxiety disorder. Which smoking cessation plan
would be most appropriate recommendation for this patient?

a. Varenicline 0.5 mg daily for 3 days; then 0.5 mg twice daily for 4 days; then 1
mg twice daily.
b. Nicotine patch 21 mg/day topically and bupropion extended release (XL) 150
mg orally twice daily.
c. Nicotine patch 14 mg/day topically
d. Nicotine patch 14 mg/day topically and nicotine gum 2 mg every 1-2 hours as
needed

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 Self Assessment Question #3:
A 68-year-old female patient has a 40 pack-year history and currently smokes 20
cigarettes daily with the first cigarette within 10 minutes of waking daily. She has a
medical history of anxiety and is working to taper and discontinue clonazepam 0.5
mg twice daily for generalized anxiety disorder. Which smoking cessation plan
would be most appropriate recommendation for this patient?

a. Varenicline 0.5 mg daily for 3 days; then 0.5 mg twice daily for 4 days; then 1
mg twice daily.
b. Nicotine patch 21 mg/day topically and bupropion extended release (XL) 150
mg orally twice daily.
c. Nicotine patch 14 mg/day topically
d. Nicotine patch 14 mg/day topically and nicotine gum 2 mg every 1-2 hours as
needed

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Obesity

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 Obesity: Cardiovascular Effects
• Affects cardiac structure and function
• Obese patients tend towards:
– increased cardiac output
– reduced systemic peripheral resistance
• BMI Categories:
– Overweight >25 kg/m2
– Obesity >30 kg/m2
• Medication-induced weight gain is a modifiable risk factor

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Medications Associated with Weight Gain

Medications that may Cause Weight Gain Weight Neutral or Loss Alternatives
Diabetes Drugs
Insulin Glimepiride, metformin, DPP4 inhibitors, acarbose, GLP-1
Sulfonylureas (glyburide and glipizide) analog, pramlintide, SGLT2 inhibitors
Meglitinides
Thiazolidinediones
Psychiatric Drugs
Antidepressants (SSRIs, TCAs, MAOIs, mirtazapine) Fluoxetine, bupropion
Antipsychotics (clozapine, olanzapine, and risperidone) Aripiprazole, quetiapine, ziprasidone
Anticonvulsants (valproic acid, gabapentin, carbamazepine) Lamotrigine, topiramate, zonisamide
Lithium
Antihypertensive Drugs
Nonselective β-blocker (namely propranolol) ACE inhibitors, ARBs, calcium channel blockers, selective β-
α-Adrenergic blockers (prazosin, clonidine) blockers

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 2019 ACC/AHA Primary Prevention Guidelines
Weight loss recommended to improve ASCVD risk profile in those who are
overweight or obese

Comprehensive lifestyle modifications, counseling, and calorie restriction are

recommended to achieve and maintain weight loss

BMI calculation recommended at least annually

Measurement of waist circumference is reasonable to stratify those patients

who may be at higher cardiometabolic risk
J Am Coll Cardiol 2019;74:e177-232

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Obesity: General Considerations

• Diet, exercise, and behavioral modifications are key
• Consider pharmacotherapy for:
– BMI greater than 30 kg/m2
– BMI greater than 27 kg/m2 with comorbidity
– Do not achieve 5% weight loss at 6 months
• Consider bariatric surgery for:
– BMI greater than 40 kg/m2
– BMI greater than 35 kg/m2 with comorbidity

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 Key Medications for Weight Loss
Phentermine/Topiramate (P/T) Naltrexone/Bupropion
MOA GABA modulator; releases norepinephrine Opioid antagonist & antidepressant
Dosing 3.75 mg(P)/23 mg(T) daily (starting) 8 mg/90 mg ER tab 1 daily x7 days,
15 mg(P)/92 mg(T) daily then twice daily for 7 days, then 2
Taper at discontinuation tabs twice daily by day 22
Key ADE Insomnia, paresthesia, tachycardia, suicidal Nausea, vomiting, diarrhea, insomnia,
ideation, SCr elevations suicidal ideation
Other REMS: requires negative pregnancy test at CYP26 inhibitor
baseline, then monthly CYP2B6 substrate

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Key Medications for Weight Loss

Tirzepatide Liraglutide (L), Semaglutide (S)
MOA Dual agonist of GLP-1 and GIP GLP-1 receptor agonist
Dosing Starting dose of 2.5 mg weekly x 4 (L): 0.6 mg SQ daily x7 days
weeks Increase weekly to 3 mg daily
Increase by 2.5 mg/week increments
every 4 weeks (S): 0.25 mg SQ weekly
Maximum dose of 15 mg/week Increase weekly to 2.4 mg SQ weekly
Key ADE Constipation, decreased appetite, Nausea, vomiting, hypoglycemia, lipase increase
diarrhea, nausea, vomiting
Other BBW: thyroid C-cell tumors in BBW: thyroid C-cell tumors in rodents; human
rodents; human relevance unknown relevance unknown

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HC10

Agent Selection for Intentional Weight Loss

Concomitant Medical Condition Avoid Medications Suggested Medications

Hypertension, heart disease Phentermine Orlistat

GLP-1 RA or SGLT2 inhibitors

Type 2 Diabetes ---
(GLP-1 RA more effective)

Phentermine
Seizure history ---
Naltrexone/bupropion

Phentermine/Topiramate,
Depression ---
Phentermine, Orlistat

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Summary of Key GLP-1 RA Trials for Weight Loss

Trial Year GLP-1 RA Control Population ∆ Kg vs. Control ∆ % Weight vs. Control
SCALE 2015 Liraglutide Placebo Obesity ± risk factors (no DM)a -8.4 vs. -2.8 -8.0 vs. -2.6
STEP-1 2021 Semaglutide Placebo Obesity ± risk factors (no DM)a -15.3 vs. -2.6 -14.9 vs. -2.41
STEP-2 2021 Semaglutide Placebo Overweight, obesity, T2DM -9.7 vs. -3.5 -9.6 vs. -3.4
STEP-3 2021 Semaglutide Placebo Obesity ± risk factors (no DM)a -16.8 vs. -6.2 -16 vs -5.7
STEP-8 2022 Semaglutide Liraglutide Obesity ± risk factors (no DM)a -15.3 vs. -6.8 -15.8 vs. -6.4

aPatientswere eligible with BMI ≥30 kg/m2 or if BMI ≥27 kg/m2 with at least 1 weight-related comorbidity (CVD,
dyslipidemia, hypertension, or obstructive sleep apnea (obstructive sleep apnea not included in SCALE))

All results statistically significant (p<0.05)

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Slide 41

HC10 removed diethypropion per reviewer comment

Heunisch, Carol, 3/1/2024
 Summary of Key GIP Trials for Weight Loss
Trial Control Population ∆ % Weight vs. Control
SURMOUNT-1 Placebo BMI ≥ 30 kg/m2 OR BMI ≥ 27 Dose dependent
kg/m2 with at least 1 weight- 15% (5mg weekly)
related complication (diabetes 19.5% (10 mg weekly)
excluded) 20.9% (15 mg weekly)
3.1% (placebo)
SURMOUNT-2 Placebo BMI ≥ 27 kg/m2 and HbA1c 7- Dose dependent
10% 12.8% (10 mg weekly)
14.7% (15 mg weekly)
3.2% (placebo)

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Summary of Key GIP Trials for Weight Loss

Trial Control Population ∆ % Weight vs. Control
SURMOUNT-3 Placebo BMI ≥ 30 kg/m2 OR BMI ≥ 27 At maximum tolerated dose (10
kg/m2 with at least 1 weight- or 15 mg weekly), additional
related complication (diabetes weight loss of 18.4% from
excluded); achieved 5% weight randomization. Placebo group
loss after 12-week lifestyle regained 2.5% of body weight
intervention
SURMOUNT-4 Placebo BMI ≥ 30 kg/m2 OR BMI ≥ 27 At end of 36-week lead-in
(36-week open-label kg/m2 with at least 1 weight- period: 21.1% mean weight loss
lead-in with related complication (diabetes At 88 weeks, those who
tirzepatide, followed excluded) remained on tirzepatide
by 52-week achieved a mean weight loss of
treatment with 21.1%, while those in the
either tirzepatide or placebo group had a mean
placebo) weight regain of 14%

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 Self Assessment Question #4:
A patient with a body mass index (BMI) of 32 kg/m2 has discussed the
role of various obesity management strategies with her provider. She
has a history of hypertension and epilepsy. Her current medications
include amlodipine 10 mg daily, lisinopril 20 mg daily, and
carbamazepine 600 mg daily. According to your clinical assessment,
which is most appropriate for this patient to use for weight loss?

a. Phentermine
b. Orlistat
c. Naltrexone/bupropion
d. Tirzepatide

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Self Assessment Question #4:

A patient with a body mass index (BMI) of 32 kg/m2 has discussed the
role of various obesity management strategies with her provider. She
has a history of hypertension and epilepsy. Her current medications
include amlodipine 10 mg daily, lisinopril 20 mg daily, and
carbamazepine 600 mg daily. According to your clinical assessment,
which is most appropriate for this patient to use for weight loss?

a. Phentermine  avoid in hypertension

b. Orlistat  avoid with narrow therapeutic index medications
c. Naltrexone/bupropion  avoid in seizures
d. Tirzepatide

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 Diabetes

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HC26

Diabetes & CV Risk Reduction: General Approach

• Assess CV risk factors annually:
– Dyslipidemia
– Hypertension
– Smoking
– Family history of premature disease
– Presence of micro- or macroalbuminuria
• Lifestyle modification is key for long-term management
• Other CV risk reduction typically follows usual recommendations
– ADA blood pressure target: <130/80 mm Hg
– ACC/AHA blood pressure target: <130/80 mm Hg

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Slide 48

HC26 Updated with 2024 guideline information

Heunisch, Carol, 3/2/2024
 2024 ADA Standards of Care: CV Risk Reduction
Recommendation Strength
Healthy lifestyle behaviors, diabetes self-management education and support, avoidance of therapeutic LOE A
inertia, and social determinants of health should be considered in the glucose-lowering management
Among patients with T2DM and established ASCVD or indicators of high CV risk, established CKD, or HF, LOE A
an SGLT2i and/or a GLP-1 receptor agonist with demonstrated CVD benefit is recommended independent
of baseline A1C, and in consideration of patient-specific factors.

SGLT2i and/or GLP-1 RA with proven CV benefit recommended independent of baseline A1c, A1c target, or
metformin use
ASCVD or high risk of ASCVD: GLP-1 RA and/or SGLT2i
HF: SGLT2i
CKD: SGLT2i; if not tolerated/contraindicated, GLP-1 RA second-line

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SGLT2i in HF, CKD, and/or CV Disease

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 Landmark Trials of SGLT2i in HFrEF
Criteria DAPA-HF (n=4744) EMPEROR-Reduced (n=3730)
Design Prospective, double-blind, placebo-controlled randomized clinical trial
LVEF ≤40% (NYHA II-IV) with elevated proBNP (cutoffs differed by trial)
Population
Receiving standard HFrEF therapy (ICD or CRT encouraged per local guidelines)
Intervention Dapagliflozin 10 mg vs. placebo Empagliflozin 10 mg daily vs placebo
Follow-Up 18.2 months (median) 16 months (median)
Primary Outcome Worsening HF or CV Death HF hospitalization or CV death
Secondary HF hospitalization or CV death HF hospitalization

N Engl J Med 2019;381:1995-2008

N Engl J Med 2020;383:1413-24

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Key Efficacy: DAPA-HF and EMPEROR-Reduced

Outcome DAPA-HF (n=4744) EMPEROR-Reduced (n=3730)
HR (95% CI) NNT HR (95% CI) NNT
Primary Outcome 0.74 (0.65-0.85) 21 0.75 (0.65-0.86) 19
HF hospitalization 0.70 (0.59-0.83) 28 0.69 (0.59-0.81) 20
CV death 0.82 (0.69-0.98) 53 0.92 (0.75-1.12) ---
HF hospitalization or CV death* 0.75 (0.65-0.85) 21 0.75 (0.65-0.86) 19
Death (all-cause) 0.83 (0.71-0.97) 44 0.92 (0.77-1.10) ---

DAPA-HF Primary outcome: HF hospitalization, HF urgent visit or CV death

EMPEROR-Reduced Primary outcome: HF hospitalization or CV death

*Primary outcome of EMPEROR-Reduced

N Engl J Med 2019;381:1995-2008
N Engl J Med 2020;383:1413-24

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 Is there other data supporting SGLT2i in HF?

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SGLT2i Effect on Traditional MACE Endpoints

EMPA-REG CANVAS DECLARE-TIMI 58
HR (95% CI)
(n=7020) (n=10,142) (n=10,186)
Empagliflozin Canagliflozin Dapagliflozin
T2DM with established CV T2DM with established CV disease T2DM with established ASCVD
Key Inclusion disease and GFR ≥30 (or ≥2 risk factors) and GFR ≥30 (or ≥2 risk factors) and CrCl ≥60
mL/min/1.72 m2 mL/min/1.72 m2 mL/min
Primary outcome* 0.86 (0.74-0.99); p=0.04 0.86 (0.75-0.97); p=0.02 0.93 (0.84-1.03); p=0.17
CV death 0.62 (0.49-0.77); p<0.001 0.87 (0.72-1.06); 0.98 (0.82-1.17)
MI (total) 0.87 (0.70-1.09); p=0.23 0.89 (0.73-1.09) 0.89 (0.77-1.01)
Stroke (total) 1.18 (0.89-1.56); p=0.26 0.87 (0.69-1.09) 1.01 (0.84-1.21)
Revascularization 0.86 (0.72-1.04); p=0.11 Not reported Not reported
Hospitalization for UA 0.99 (0.74-1.34); p=0.97 Not reported Not reported
*EMPA-REG: CV death, MI, CVA *CANVAS: CV death, MI, CVA *DECLARE: CV death, MI, CVA and CV death or HF hospitalization

N Engl J Med 2015;373:2117-28 N Engl J Med 2017;377:644-57 N Engl J Med 2019;380:347-57

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27
 SGLT2i Effect on HF Endpoints in CV Trials
EMPA-REG CANVAS DECLARE-TIMI 58
(n=7020) (n=10,142) (n=10,186)
Empagliflozin Canagliflozin Dapagliflozin
HF hospitalization 0.65 (0.50-0.85), p=0.002 0.67 (0.52-0.87) 0.73 (0.61-0.88)
HF hospitalization
0.66 (0.55-0.79); p<0.001 0.78 (0.67-0.91) 0.83 (0.73-0.95); p=0.005
or CV death

N Engl J Med 2015;373:2117-28 N Engl J Med 2017;377:644-57 N Engl J Med 2019;380:347-57

55

Are these really HF medications?

56

28
 Totality of HF-Related Outcomes: Efficacy
Agent Trial (n) Year N Population HF Hospitalization Mortality
Canagliflozin CANVAS 2017 10,142 T2DM & CVD (or risk factors) 
Canagliflozin CREDENCE 2019 4,401 T2DM, eGFR 30-90, albuminuria 
Dapagliflozin DECLARE-TIMI 2019 17,160 T2DM & ASCVD (or risk factors) 
Dapagliflozin DAPA-HF 2019 4,744 HFrEF (NYHA II-IV), ↑ proBNP  
Dapagliflozin DAPA-CKDa 2020 4,304 T2DM, eGFR 25-75, albuminuria  
Empagliflozin EMPA-REG 2015 7,020 T2DM & CV disease  
Empagliflozin EMPEROR-R 2020 3,730 HFrEF (NYHA II-IV), ↑ proBNP 
Empagliflozin EMPEROR-P 2021 5,988 HFpEF (NYHA II-IV), ↑ proBNP 
Ertugliflozin VERTIS-CV 2020 8,246 T2DM & ASCVD 
Sotagliflozin SOLOIST-WHFb 2020 1,222 HFrEF hospitalization & T2DM 
Sotagliflozin SCOREDb 2020 10,584 T2DM, eGFR 25-60, risk factors 
N refers to total N undergoing randomization from all arms
Outcomes reported as total occurrence or time-to-first event, depending on the trial; mortality refers to both all-cause mortality and CV mortality
aDAPA-CKD found reductions in all-cause mortality, but not CV mortality; other trials were consistent for both mortality outcomes
bSOLOIST-WHF and SCORED reported combined HF hospitalization and urgent care visit for HF (did not report “HF hospitalization” alone)

57

Are these medications safe & effective in CKD?

58

29
 Landmark Trials of SGLT2i in Patients with CKD
Criteria DAPA-CKD (n=4304) CREDENCE (n=4401)
Design Prospective, double-blind, placebo-controlled randomized clinical trial
Adults (with or without T2DM) eGFR 25-75 Age ≥30 years, T2DM (HbA1c 6.5-12%) with
Population
mL/min/1.73 m2 and albuminuria eGFR 30 to <90 mL/min/1.73 m2 albuminuria
Intervention Dapagliflozin 10 mg daily vs placebo Canagliflozin 100 mg daily vs placebo
Follow-Up 2.4 years (median) 2.62 years (median)
decline of 50% in eGFR, onset of ESRD, or ESRD, doubling of serum creatinine for ≥30
Primary Outcome
renal or CV death (time-to-event) days, or death from renal or CV causes
Renal Outcome: decline of 50% in eGFR,
Secondary CV death or HF hospitalization (hierarchical)
onset of ESRD or renal death (hierarchical)
CV Outcome: heart failure hospitalization or
Secondary CV death, MI, stroke (hierarchical)
CV death (hierarchical)

N Engl J Med 2019;380:2295-306

N Engl J Med 2020;383:1436-46

59

Key Efficacy: DAPA-CKD and CREDENCE

Outcome DAPA-CKD (n=4304) CREDENCE (n=4401)
HR (95% CI) NNT HR (95% CI) NNT
Primary Outcome 0.61 (0.51-0.72) 19 0.70 (0.59-0.82) 23
Onset of ESRD 0.64 (0.50-0.82) 42 0.68 (0.54-0.86) 46
HF hospitalization or CV death 0.71 (0.55-0.92) 56 0.69 (0.57-0.83) 30
CV death, MI, stroke Not reported 0.80 (0.67-0.95) 44
CV Death 0.81 (0.58-1.12) --- 0.78 (0.61-1.00) ---
Death (all-cause) 0.69 (0.53-0.88) 48 0.83 (0.68-1.02) ---

DAPA-CKD Primary outcome: decline of 50% in eGFR, onset of ESRD, or renal death or CV death
CREDENCE Primary outcome: onset of ESRD, doubling of serum creatinine for ≥30 days, or death from renal or CV causes

N Engl J Med 2019;380:2295-306

N Engl J Med 2020;383:1436-46

60

30
 Self-Assessment Question #5
A 65-year-old woman with type 2 diabetes is currently taking
metformin 1000 mg twice daily and liraglutide 1.8 mg daily. Her
hemoglobin A1c is 8.4%. Which of the following would be best to
reduce her cardiovascular risk?

a. Glipizide 2.5 mg daily

b. Empagliflozin 10 mg daily
c. Repaglinide 1 mg before meals
d. Saxagliptin 2.5 mg daily

61

Self-Assessment Question #5
A 65-year-old woman with type 2 diabetes is currently taking
metformin 1000 mg twice daily and liraglutide 1.8 mg daily. Her
hemoglobin A1c is 8.4%. Which of the following would be best to
reduce cardiovascular risk?

a. Glipizide 2.5 mg daily  no demonstrated CV benefit

b. Empagliflozin 10 mg daily
c. Repaglinide 1 mg before meals  no demonstrated CV benefit
d. Saxagliptin 2.5 mg daily  may increase risk of HF

62

31
 Aspirin in Primary Prevention

63

Early Aspirin Primary Prevention Trials

British Doctors’ Trial (BDT) Physicians’ Health Study (PHS)
N=5139 British male physicians; 6-year
N=22,071 male US physicians; 5-year follow-up
follow-up
Design
Randomized unblinded 2:1 to aspirin 500 mg Randomized, double-blind to aspirin 325 mg every
daily or to avoid aspirin between 1978-1984 other day or placebo in 1984; terminated 1987

Key Nonfatal MI: 42.5 vs 43.3 (p>0.05) Nonfatal MI: RR 0.59 (95% CI 0.47-0.74, p<0.00001)
Efficacy Fatal MI: or stroke: 63.2 vs 62.3 (p>0.05) Fatal MI: RR 0.34 (95% CI 0.15-0.75; p=0.007)
Results Vascular death: 4.3% vs. 4.6% (p>0.05) Vascular death: RR 0.94 (95% CI 0.60-1.54; p=0.87)
Ulcer with bleeding: RR 1.77 (95% CI 1.07-2.94; p=0.04)
Safety Peptic ulcer: 46.8 vs 29.6 (p<0.05)
Blood transfusion: RR 1.71 (95% CI, 1.09-2.69; p=0.02)

MI = myocardial infarction
Br Med J 1988;296:313-6 N Engl J Med 1989;321:129-135

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32
 Key Quotes from the Authors: BDT and PHS
“Our principal hope when we began this study was that vascular events
and vascular death might be avoided. In this respect the results are not
encouraging, though the confidence intervals for the effect of treatment
on stroke, myocardial infarction, or vascular death are wide (ranging
between a 16% benefit and a 26% adverse effect).” –BDT Authors

“For the general public, however, the decision whether to take aspirin to
reduce the risks of cardiovascular disease should be an individual
judgment made only with the advice of a physician or other health care
provider. In the making of this decision, the cardiovascular risk profile of
the patient and the risks and benefits of the drug should be weighed.”
–PHS Authors
Br Med J 1988;296:313-6 N Engl J Med 1989;321:129-135

65

2009 ATT Meta-Analysis of Aspirin In Primary Prevention

Outcome, n (% per year) Aspirin Control Rate Ratio (95% CI) P-Value Effect
Non-fatal MI 596 (0.18) 756 (0.23) 0.77 (0.67-0.89) NR 
CHD death 372 (0.11) 393 (0.12) 0.95 (0.78-1.15) NS
Any major coronary event 934 (0.28) 1115 (0.34) 0.82 (0.75-0.90) 0.00002 
Non-fatal stroke 533 (0.17) 597 (0.18) 0.92 (0.79-1.07) NS
Fatal stroke 119 (0.04) 98 (0.03) 1.21 (0.84-1.74) NS
Any Stroke 655 (0.20) 682 (0.21) 0.95 (0.85-1.06) 0.4
Vascular death 619 (0.19) 637 (0.19) 0.97 (0.87-1.09) 0.7
Any serious vascular event 1671 (0.51) 1883 (0.57) 0.88 (0.82-0.94) 0.0001 

Takeaway: modest reduction in total vascular events (0.51% vs. 0.57% per year) driven by reduction in nonfatal MI
(0.18% vs 0.23% per year) from all RCTs up to 2009

Lancet 2009;373:1849-60

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33
 2018: ARRIVE, ASCEND, ASPREE

67

ARRIVE Trial: Overview

Key Inclusion Criteria
Key Exclusion Criteria
Males ≥ 55 years old with 2-4 risk factors
History of vascular events
Females ≥ 65 years old with ≥ 3 risk factors
Coronary Bypass Surgery
Moderate CV Risk (10-year CHD risk of 10-20%)
Heart Failure, Diabetes
Risk factors:
Indication for antiplatelets
Smoking
Indication for anticoagulants
Uncontrolled lipids
Frequent use of NSAIDs
SBP >140 mm Hg or taking meds
High risk of or history of GI bleeding
Family history of CV disease

ARRIVE Trial Design Summary

Design Prospective, randomized, double-blind, placebo-controlled, international
Intervention Aspirin 100 mg daily vs placebo (n=12,546)
Primary Outcome MI, stroke, CV death, unstable angina, or transient ischemic attack (TIA)
Safety Outcome GUSTO bleeding (severe, moderate, mild)
Follow-Up Median 1858 days or 5.1 years; July 2007 to November 2016
Lancet 2018; 392:1036-1046

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34
 ARRIVE Trial: Results
Aspirin Placebo NNT
Outcome, n (%) HR (95% CI) P-Value Effect
(n=6270) (n=6276) NNH
Primary Outcome 268 (4.29) 281 (4.48) 0.96 (0.81-1.13) 0.6038 ---
Myocardial Infarction 95 (1.52) 112 (1.78) 0.85 (0.64-1.11) 0.2325 ---
Stroke 75 (1.20) 67 (1.07) 1.12 (0.80-1.55) 0.5072 ---
CV Death 38 (0.61) 39 (0.62) 0.97 (0.62-1.52) 0.9010 ---
Unstable Angina 20 (0.32) 20 (0.32) 1.00 (0.54-1.86) 0.9979 ---
Transient Ischemic Attack 42 (0.67) 45 (0.72) 0.93 (0.61-1.42) 0.7455 ---
GI Bleeding 61 (0.97) 29 (0.46) 2.11 (1.36-3.28) 0.0007 197 

Results consistent across all subgroups

Lancet 2018; 392:1036-1046

69

ASCEND Trial: Overview

Inclusion Criteria
Exclusion Criteria
Men or women ≥ 40 years old
Aspirin indication
Diabetes mellitus (any type)
Aspirin contraindication
No known history of CV disease
Any condition that might limit
Substantial uncertainty if aspirin would confer
adherence ≥ 5 years
worthwhile benefit

ASCEND Trial Design Summary

Design Randomized, double-blind placebo-controlled 2x2 factorial trial in the UK
Aspirin 100 mg daily or placebo (n=15,480)
Intervention
1 gram n-3 fatty acid (460 mg EPA, 380 mg DHA) vs. 1 gram placebo (olive oil)
Primary Outcome (original) MI, stroke (non-hemorrhagic), or CV death
Primary Outcome (modified) MI, stroke (non-hemorrhagic), TIA, or CV death
Safety Outcome Any major bleeding
Follow-Up Mean 7.4 years from June 2005 to July 2011
N Engl J Med 2018;379:1529-1539

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35
 ASCEND Trial: Key Results
Aspirin Placebo NNT
Outcome, n (%) RR (95% CI) P-Value Effect
(n=7740) (n=7740) NNH
MI, Stroke, CV Death 542 (7.0) 587 (7.6) 0.92 (0.82-1.03) NS ---
MI, Stroke, TIA, CV Death 658 (8.5) 743 (9.6) 0.88 (0.79-0.97) 0.01 91 
Myocardial Infarction 191 (2.5) 195 (2.5) 0.98 (0.80-1.19) NS ---
Stroke (ischemic) 202 (2.6) 229 (3.0) 0.88 (0.73-1.06) NS ---
TIA 168 (2.2) 197 (2.5) 0.85 (0.69-1.04) NS ---
CV Death 197 (2.5) 217 (2.8) 0.91 (0.75-1.10) NS ---
Major Bleeding (any) 314 (4.1) 245 (3.2) 1.29 (1.09-1.52) 0.003 112 
Serious GI Bleeding 137 (1.8) 101 (1.3) 1.36 (1.05-1.75) NR 200 
Intracranial Hemorrhage 55 (0.7) 45 (0.6) 1.22 (0.82-1.81) NS ---
Results consistent across all subgroups
RR = Risk Rate

N Engl J Med 2018;379:1529-1539

71

ASPREE Trial: Overview

Inclusion Criteria Exclusion Criteria
Men and women ≥ 70 years old (or ≥ 65 years old if black Aspirin contraindication
or Hispanic in the United States) Known high bleeding risk
Community-dwelling Dementia
No know cardiovascular or cerebrovascular disease Substantial physical disability
Free from any chronic illness limiting 5-year survival Modified MMSE score < 78

ASPREE Trial Design Summary

Design Prospective, double-blind, placebo-controlled trial in Australia and US
Intervention Aspirin 100 mg daily or placebo (n=19,114)
Primary Outcome Survival free from dementia or persistent physical disability
Primary Composite Death, dementia, or persistent physical disability
Safety Outcome Major hemorrhage
Follow-Up Median 4.7 years; March 2010 to December 2014 (terminated early)

N Engl J Med 2018;379:1499-1508 N Engl J Med 2018;379:1509-1518 N Engl J Med 2018;379:1519-1528

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36
 ASPREE Trial: Key Results
Aspirin Placebo NNT
Outcome, n (rate per 1000 person-year) HR (95% CI) Effect
(n=9525) (n=9589) NNH
Primary Outcome 921 (21.5) 914 (21.2) 1.01 (0.92-1.11) ---
Death (any cause) 480 (11.2) 431 (10.0) Not Reported --- ---
Dementia 274 (6.7) 275 (6.9) 0.98 (0.83-1.15) ---
Physical Disability 167 (4.9) 208 (5.8) 0.85 (0.70-1.03) ---
CV Death 91 (1.0) 112 (1.2) 0.82 (0.62-1.08) ---
CHD Death, MI, Stroke 448 (10.7) 474 (11.3) 0.95 (0.83-1.08) ---
Major Hemorrhage 361 (8.6) 265 (6.2) 1.38 (1.18-1.62) 98 
Intracranial Bleeding 107 (2.5) 72 (1.7) 1.50 (1.11-2.02) 271 
GI Bleeding (upper) 89 (2.1) 48 (1.1) 1.87 (1.32-2.66) 233 

Results consistent across all subgroups

Note: higher overall mortality seen with aspirin due to higher rates of cancer-related death
N Engl J Med 2018;379:1499-1508 N Engl J Med 2018;379:1509-1518 N Engl J Med 2018;379:1519-1528

73

Guideline Summary
Guideline Summary of Recommendations: Aspirin for Primary Prevention Strength
Antiplatelet therapy (e.g., with aspirin) is not recommended in individuals without CVD due to the
ESC Class III, LOE: B
increased risk of major bleeding
(2016)
Antiplatelet therapy is not recommended for people with DM who do not have CVD. Class III ,LOE: A
Low-dose aspirin (75-100 mg orally daily) might be considered for the primary prevention of ASCVD
Class IIb, LOE: A
among select adults 40 to 70 years of age at higher ASCVD risk but not at increased bleeding risk
ACC/AHA Low-dose aspirin (75-100 mg orally daily) should not be administered on a routine basis for the Class III (Harm)
(2019) primary prevention of ASCVD among adults >70 years of age LOE: B-R
Low-dose aspirin (75-100 mg orally daily) should not be administered for the primary prevention of Class III (Harm)
ASCVD among adults of any age who are at increased risk of bleeding LOE: C-LD
Aspirin therapy (75-162 mg/day) may be considered as a primary prevention strategy in those with
ADA
diabetes who are at increased cardiovascular risk, after a discussion with the patient on the Grade A
(2022)
benefits versus increased risk of bleeding
ESC In patients with DM at high or very high CVD risk, low-dose aspirin may be considered for primary
Class II, LOE: B
(2021) prevention in the absences of clear contraindications
Eur Heart J 2016;37:2315-81 Diabetes Care 2022;45(Suppl 1):s144-s174 J Am Coll Cardiol 2019;74:e177-232 Eur Heart J 2021;42:3227-337

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 Effective Primary Preventions Strategies
Hypertension Smoking
Lipid Therapy
Goals Cessation

Glycemic Lifestyle Diet &

Control Modifications Exercise

Meta-analysis of aspirin for primary prevention studies

Non-Fatal MI Total CVD Events
Publication Year
OR (95% CI) Effect P-Value OR (95% CI) Effect P-Value
After 2000 0.98 (0.84-1.14) 0.92 (0.83-1.01)
<0.001 0.66
Before 2000 0.67 (0.56-0.81)  0.89 (0.82-0.97) 
Arch Intern Med 2013;172:209-216

75

Patient Case 1
A 63-year-old male with hypertension, hyperlipidemia, and former
tobacco use presents to his primary care physician for a routine
wellness check. His BMI is 28 kg/m2, his blood pressure is 145/87 mm
Hg, and his calculated 10-year CV risk is 13% (using Framingham score)
and 17% (using PCE), respectively. What is the best recommendation for
aspirin in primary prevention for this patient?

a. Initiate aspirin 81 mg daily

b. Initiate aspirin 325 mg every other day
c. Initiate aspirin 325 mg daily
d. Aspirin for primary prevention is not indicated in this patient

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38
 Patient Case 1
A 63-year-old male with hypertension, hyperlipidemia, and former
tobacco use presents to his primary care physician for a routine
wellness check. His BMI is 28 kg/m2, his blood pressure is 145/87 mm
Hg, and his calculated 10-year CV risk is 13% (using Framingham score)
and 17% (using PCE), respectively. What is the best recommendation for
aspirin in primary prevention for this patient?

a. Initiate aspirin 81 mg daily  dose studied in ARRIVE

b. Initiate aspirin 325 mg every other day  dose not recommended
c. Initiate aspirin 325 mg daily  dose not recommended
d. Aspirin for primary prevention is not indicated in this patient

77

Complementary Therapies: Omega-3 Fatty Acids

78

39
 Recommendations for Omega-3 Fatty Acids?
2016 ECDP 2017 ACC
2013 ACC/AHA 2018 AHA/ACC 2019 ESC Lipid
Non-Statin Focused Update
Lipid Guidelines Lipid Guidelines Guidelines
Therapies on 2016 ECDP

--- --- --- --- Yes

ECDP = expert consensus decision pathway

79

2018 Meta-analysis of Omega-3 Fatty Acid Trials

Criteria Details
Search Systematic search of RCTs in PubMed and Medline with manual reference review
RCT of marine-derived very-long chain omega-3 fatty acid vs placebo or active control
Criteria
At least 500 patients and at least one-year follow-up
Endpoints Nonfatal MI; CHD death; stroke; revascularization; MACE (composite); all-cause mortality
Trials 10 trials included, totaling 77,917 participants; 8 of 10 trials had low risk for bias
Data extraction 9 of 10 trials provided aggregated study-level data (JELIS trial declined)
Doses EPA 226-1800 mg/day; DHA 0-1700 mg/day; weighted mean duration 4.4 years
CHD Death: RR 0.93 (99% CI 0.83-1.03); p=0.05
Results Nonfatal MI: RR 0.97 (99% CI 0.87-1.08); p=0.43
Any CHD event: RR 0.96 (95% CI 0.90-1.01); p=0.12
Note ASCEND, VITAL, and REDUCE-IT were published after this meta-analysis and are not included

JAMA Cardiol 2018;3(3):225-34 CHD = coronary heart disease; MACE = major adverse cardiovascular events; RCT = randomized controlled trial

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40
 Summary of Recent Trials with Omega-3 Fatty Acids
Characteristic ASCEND (n=15,480) VITAL (n=25,304)
Design Randomized, prospective, placebo-controlled 2x2 factorial trial
Age ≥40 years with DM and no evidence of Age ≥50 years (men) or ≥55 (women) with
Population
CV disease no evidence of CV disease
Intervention 1 gram n-3 fatty acid (460 mg EPA, 380 mg DHA) vs. 1 gram placebo (olive oil)
Follow-Up Median 7.4 years Median 5.3 years
Nonfatal MI or stroke, TIA, or cardiovascular
Primary Endpoint MI, stroke, or CV death
death (TIA added during recruitment)
Primary Outcome 8.9% vs 9.2%; RR 0.97 (0.87-1.08; p=0.55) 2.98% vs 3.24%; HR 0.92 (0.80-1.060; p=0.24)

N Engl J Med 2018;379:1540-50 N Engl J Med 2019;380:23-32

81

Recommendations for Omega-3 Fatty Acids?

2016 ECDP 2017 ACC
2013 ACC/AHA 2018 AHA/ACC 2019 ESC Lipid
Non-Statin Focused Update
Lipid Guidelines Lipid Guidelines Guidelines
Therapies on 2016 ECDP

--- --- --- --- Yes

ECDP = expert consensus decision pathway

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41
 REDUCE-IT Trial: Overview
Inclusion Criteria: Exclusion Criteria:
Age ≥45 years with established CV disease, or Severe heart failure or active severe liver disease
Age ≥50 years with DM and ≥1 risk factor Hemoglobin A1c ≥10%
and Planned coronary intervention or surgery
LDL 41-100 mg/dL and TG 200-499 mg/dL History of acute or chronic pancreatitis
On stable dose of statin for ≥4 weeks Icosapent ethyl, fish, or shell fish hypersensitivity

Criteria Details
Design Prospective, randomized, double-blind, placebo-controlled international trial
Icosapent ethyl 2 grams PO BID (4 grams daily) vs. placebo (mineral oil)
Intervention
Stratified by secondary or primary prevention, ezetimibe use, geographic region
Enrollment N=8179 patients followed for median 4.9 years
Primary Outcome CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina
Secondary Outcome CV death, nonfatal MI, or nonfatal stroke (protocol amendment)
Statistics 1612 endpoints; 90% power to detect 15% difference; planned n=7990; α=0.0437
N Engl J Med 2019;380:11-22

83

REDUCE-IT Trial: Key Results

Icosapent ethyl Placebo NNT
Outcome, n (%) Hazard Ratio (95% CI) P-value Effect
(n=4089) (n=4090) NNH
Primary endpoint 705 (17.2) 901 (22.0) 0.75 (0.68-0.83) <0.001 21 
Secondary endpoint 459 (11.2) 606 (14.8) 0.74 (0.65-0.83) <0.001 28 
Cardiovascular death 174 (4.3) 213 (5.2) 0.80 (0.66-0.98) 0.03 112 
Fatal or nonfatal MI 250 (6.1) 355 (8.7) 0.69 (0.58-0.81) <0.001 39 
Fatal or nonfatal stroke 98 (2.4) 134 (3.3) 0.72 (0.55-0.93) 0.01 112 
All-cause mortality 274 (6.7) 310 (7.6) 0.87 (0.74-1.02) NR ---
Atrial fibrillation 215 (5.3) 159 (3.9) Not reported 0.003 72 

Primary endpoint = CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina
Secondary endpoint = CV death, nonfatal MI, or nonfatal stroke N Engl J Med 2019;380:11-22

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42
 STRENGTH Trial: Overview
Inclusion Criteria:
Exclusion Criteria:
Adults at high CV risk (below), LDL <100 mg/dL, TG 180-500 mg/dL
Ischemic CV event within 30 days,
1. Established ASCVD, or
fibrates, taking > 1 gram of EPA/DHA,
2. DM, ≥ 40 (men) or 50 (women) years,& ≥1 risk factors, or
weight loss medications
3. ≥50 (men) or 60 (women) years with ≥1 risk factors

Criteria Details
Design Prospective, randomized, double-blind, placebo-controlled international trial
Intervention Omega-3 CA 4 grams (75% EPA, 25% DHA) daily vs. placebo (corn oil)
N=13,078 patients followed for median 3.5 years (stopped early due to futility)
Enrollment
≥50% required to be secondary prevention; all patients required to take statin ≥ 4 weeks
Primary Outcome CV death, MI, stroke, revascularization, unstable angina
Secondary Outcome CV death, MI, stroke, revascularization, unstable angina in patients with CVD
Statistics 1600 endpoints; 90% power to detect 15% difference; planned n=13,000 over 4.5 years
JAMA 2020;324:2268-80 Omega-3 CA = Omega-3 carboxylic acid

85

STRENGTH Trial: Key Results

Omega-3 CA Placebo NNT
Outcome, n (%) HR (95% CI) P-Value Effect
(n=6539) (n=6539) NNH
Primary: MACE 785 (12) 795 (12.2) 0.99 (0.90-1.09) 0.84 n/a
CV Death 228 (3.5) 211 (3.2) 1.09 (0.90-1.31) 0.37 n/a
MI (nonfatal) 218 (3.3) 226 (3.5) 0.97 (0.81-1.17) 0.77 n/a
Stroke (nonfatal) 142 (2.2) 125 (1.9) 1.14 (0.90-1.45) 0.28 n/a
Revascularization 414 (6.3) 441 (6.7) 0.94 (0.83-1.08) 0.41 n/a
Unstable Angina 87 (1.3) 104 (1.6) 0.84 (0.63-1.12) 0.23 n/a
MACE in CVD 569 (15.6) 610 (16.6) 0.94 (0.84-1.05) 0.27 n/a
CV events in CVD 383 (10.5) 385 (10.5) 1.01 (0.87-1.16) 0.94 n/a
Coronary events in CVD 417 (11.5) 493 (13.4) 0.85 (0.75-0.97) 0.02 53 
Atrial fibrillation 144 (2.2) 86 (1.3) 1.69 (1.29-2.21) <0.001 112 

JAMA 2020;324:2268-80 Omega-3 CA = Omega-3 carboxylic acid

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43
 Where do we go from here?
STRENGTH also used high-dose, high-purity EPA and included
patients with elevated triglycerides

STRENGTH failed to demonstrate meaningful benefit

Did DHA component affect results?

Did mineral oil placebo affect results?

Unlikely that magnitude of potential DHA harm equaled

magnitude of potential EPA benefit

Only definitive answer is to conduct a trial of icosapent ethyl vs.

corn oil placebo
JAMA 2020;324:2280-1

87

2019 ESC Lipid Guidelines: Omega-3 FA Summary

Statement Grade
Statins are first drug of choice to reduce CVD risk in high-risk individuals with TG >200
Class I, LOE: B
mg/dL
In high-risk patients with TG 135-499 mg/dL despite statin therapy, icosapent ethyl 2
Class IIa, LOE: B
grams twice daily should be considered in combination with a statin
Oral supplementation with highly purified n-3 PUFAs reduced mortality in survivors of MI in one study (GISSI-P) but
failed to affect clinical outcomes in subsequent trials using contemporary secondary prevention therapies. A recent
meta-analysis of available RCTs showed no reduction in mortality, MI, or major vascular events associated with n-3
PUFAs, including the subgroup of patients with known CAD. Therefore, routine treatment with n-3 PUFAs cannot be
recommended. (in patients with ACS)

Icosapent ethyl FDA indication (December 2019): as an adjunct to maximally tolerated statin therapy to reduce the
risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult
patients with triglyceride levels ≥150 mg/dL and established cardiovascular disease or diabetes mellitus and ≥2
additional risk factors for cardiovascular disease

Eur Heart J 2020; 41:111-188 PUFA = polyunsaturated fatty acid

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 Patient Case 2
A 52-year-old female with diabetes, hypertension and obesity presents to your
CV risk reduction clinic. Her current medications include atorvastatin 40 mg
daily, empagliflozin 25 mg daily, lisinopril 20 mg daily and metformin 1000 mg
twice daily. A recent lipid panel includes LDL 80 mg/dL and triglycerides 220
mg/dL. Her hemoglobin A1c is 7.8%. She asks about taking fish oil. Which of
the following is most appropriate for this patient?

a. Omega-3 fatty acid 1 gram daily

b. Omega-3 carboxylic acid 2 grams twice daily
c. Icosapent ethyl 2 grams twice daily
d. Omega-3 fatty acids are not indicated in this patient

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Patient Case 2
A 52-year-old female with diabetes, hypertension and obesity presents to your
CV risk reduction clinic. Her current medications include atorvastatin 40 mg
daily, empagliflozin 25 mg daily, lisinopril 20 mg daily and metformin 1000 mg
twice daily. A recent lipid panel includes LDL 80 mg/dL and triglycerides 220
mg/dL. Her hemoglobin A1c is 7.8%. She asks about taking fish oil. Which of
the following is most appropriate for this patient?

a. Omega-3 fatty acid 1 gram daily  VITAL and ASCEND trial

b. Omega-3 carboxylic acid 2 grams twice daily  STRENGTH trial
c. Icosapent ethyl 2 grams twice daily  REDUCE-IT trial
d. Omega-3 fatty acids are not indicated in this patient  icosapent ethyl

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 Key Takeaways

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Key Takeaways
CV risk should be assessed routinely, and shared decision-making should be utilized

Diet, exercise, weight management, smoking cessation, blood pressure control and lifestyle
modifications remain cornerstone of lifelong CV health
PCE is the most recommended CV risk assessment tool by American guidelines (but other tools exist
and may be helpful in certain patients)
SGLT2i should be considered for all patients with HFrEF and/or CKD (with or without DM)

Aspirin generally not recommended for primary prevention due to increased bleeding risk and lack of
consistent CV benefit (especially in modern populations)
Icosapent ethyl may be considered for select patients for primary or secondary prevention, but other
omega-3 fatty acids do not improve CV outcomes

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 Primary Prevention of Cardiovascular Disease
and Public Health

Carol Heunisch, Pharm.D., BCPS, BCCP

Director, Drug Policy and Education, North Region
Endeavor Health
Highland Park, IL

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