Cardiovascular Diseases Update for Practicing Pharmacists · 2018. 4. 1. · . 2016 ACC/AHA/HFSA...

Tamara Goldberg Pharm.D., BCPS

Associate Professor of Pharmacy Practice

Arnold & Marie Schwartz College of Pharmacy

Long Island University

Cardiovascular Diseases Update for

Practicing Pharmacists

Objectives

▪ Discuss updates in the diagnosis and management of various cardiovascular

conditions

▪ Discuss important counseling points for patients with cardiovascular diseases

▪ Provide treatment recommendations for a patient with cardiovascular disease

Question #1

Changes in the recommendations of the JNC8 guidelines as

compared to those in the JNC7 guidelines include:

A. Less intensive blood pressure goals for patients 60 years of age

or older and those with diabetes or chronic kidney disease

B. Removal of beta-blockers from the list of preferred initial

therapies for the management of hypertension in the general

population

C. Addition of preferred drug classes for the initial management of

hypertension in black patients

D. All of the above

▪ 92.1 million American adults live with some

form of cardiovascular disease or the after-

effects of stroke

▪ Direct and indirect costs of cardiovascular

diseases and stroke are estimated to total

more than $316 billion

▪ ~2,200 Americans die of cardiovascular

disease each day

▪ More deaths than cancer and respiratory

diseases combined

Heart Disease: Scope and Impact

Benjamin EJ, Blaha MJ, Chiuve SE, et al. American Heart Association Statistics Committee and Stroke Statistics

Subcommittee. Heart disease and stroke statistics—2017 update: a report from the American Heart Association

Circulation. 2017;135:e146-e603.

2013 update 2016 Update

Updates in the Management of Heart Failure

▪Heart Failure with Reduced Ejection Fraction (HFrEF) ≤40%

▪Heart Failure with Preserved Ejection Fraction (HFpEF) ≥50%▪ HFpEF, Borderline 41% -49%

▪ HFpEF, Improved >40% ▪

▪2016 ACC/AHA/HFSA Focused

Update on New Pharmacological

Therapy for Heart Failure:

▪New Epidemiology

▪New Therapies

▪New Guidelines

▪New Phenotype

Yancy, C. Jessup M, Bozkurt B. et al. JACC 2013

Updates in the Management of Heart Failure

European Society of Cardiology 2016 Guidelines

Type of HF HFrEF HFmrEF HFpEF

Symptoms ± signs Symptoms ± signs Symptoms ± signs

LVEF <40% LVEF 40-49% LVEF >50%

1. Elevated levels of natriuretic

peptides

2. At least 1 additional criteria

a. Relevant structural heart

disease

b. Diastolic dysfunction

1. Elevated levels of

natriuretic peptides

2. At least 1 additional

criteria

a. Relevant structural heart

disease

b. Diastolic dysfunction

Heart Failure: Important Practice Points▪ Heart failure patients should be on a regimen consisting of : ACEI/or ARBs, BB, diuretic

▪ In symptomatic HF patients despite standard therapy, consider:

▪ Sacubitril/valsartan

▪ Aldosterone antagonist

▪ Hydralazine/Isosorbidedinitrate

▪ Ivabridine?

▪ Digoxin

▪ Avoid medications that could exacerbate HF: NSAIDs, glucocorticoids, thiazolidinediones

▪ Implement non-pharmacologic therapy

▪ Smoking cessation

▪ Decrease consumption of dietary sodium

▪ Fluid <2L/day

New FDA-Approved Sacubitril/ValsartanBrand Name Entresto

Indication To reduce the risk of CV death and HF hospitalization in patients with HF

with reduced ejection fraction

Dosage Start: 49/51 mg twice daily. Double the dose after 2–4 weeks as tolerated

to maintenance dose of 97/103 mg twice daily

Renal/hepatic impairment For patients not currently taking an ACEI or ARB, or for those with severe

renal impairment (eGFR <30 mL/min/1.73 m2)or moderate hepatic

impairment, start with 24/26 mg twice daily

Switching from an ACE

inhibitor

Stop ACE inhibitor for 36 hours before starting treatment

Contraindications History of angioedema related to previous ACE inhibitor or ARB,

concomitant use of ACE inhibitors, concomitant use of aliskiren in patients

with diabetes. WARNING – pregnancy, hyperkalemia

Side effects Hypotension, hyperkalemia, cough, dizziness, renal failure, and

angioedema (0.5% Sac/Val vs. 0.2% Enalapril)

http://www.pdr.net/full-prescribing-information/entresto?druglabelid=3756. Accessed April 24th, 2017.

Effects of Neprilysin Inhibition in Heart Failure

Endogenous vasoactive

peptides(natriuretic peptides,

adrenomedullin,

bradykinin, substance P,

calcitonin gene-related peptide)

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Sodium retention

Neprilysin

Inactive metabolites

Neprilysin

inhibition

PARADIGM-HF: Angiotensin–Neprilysin Inhibition

versus Enalapril in Heart Failure

▪ Evaluated the superiority of Entresto vs enalapril on

HF hospitalization and mortality reduction in HFrEF

patients

▪ Provided evidence to support the replacement of

ACEI/ARBs with Entresto in the management of

chronic HFrEF

▪ 70% of study population were NYHA class II

▪ The primary end point

▪ First event in the composite of CV death or HF

hospitalization

McMurray J et al. N Engl J Med. 2014;371:993-1004.

PARADIGM-HF: Primary Endpoint of CV Death or

Heart Failure HospitalizationNumber needed to treat = 21

McMurray JJV, et al. N EnglJ Med. 2014;371:993-1004.

1117 events (26.5%)

914 events (21.8%)

PARADIGM-HF: Effect of Sac/Val vs. Enalapril

on the Primary Endpoint and Its Components

Sac/Val

(n=4187)

Enalapril

(n=4212)

Hazard Ratio

(95% CI)

p- Value

Primary

endpoint

914 (21.8%) 1117 (26.5%) 0.80 (0.73–0.87) <0.001

Cardiovascular

death

558 (13.3%) 693 (16.5%) 0.80 (0.71–0.89) <0.001

Hospitalization

for heart failure

537 (12.8%) 658 (15.6%) 0.79 (0.71–0.89) <0.001

McMurray JJV, et al. N EnglJ Med. 2014;371:993-1004.

The ACC, AHA, and HFSA Guideline Update

▪Sac/Val may be recommended as an alternative to ACEI or ARBs to reduce

morbidity and mortality in patients with chronic HFrEF

▪ Specifically advises switching symptomatic HFrEF patients to Sac/Val to further reduce

morbidity and mortality

▪ Do NOT administer to patients within 36 hours of the last dose of ACEI

▪ Do NOT administer to patients with a history of angioedema

. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for

the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on

Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016;134

Practice Points for Pharmacists on the Use of

Sacubitril/Valsartan

▪Starting dose is 24/26 mg twice daily

▪ If the patient is tolerating a full dose of ACEI or ARB start with 49/51 mg twice daily

▪ Target dose is 97/103 mg twice daily

▪After 2-4 weeks titrate up to next dose with ultimate goal to achieve target dose

▪Monitor

▪ SBP, renal function and K+ as you would with ACEI or ARB

▪Space out dosing from other vasoactive medications if needed

▪Adjust diuretics doses based on volume status

Ivabradine

Brand name Corlanor

Indication

To reduce the risk of hospitalization for worsening HF in patients with

stable, symptomatic chronic HF with LVEF ≤35% who are in sinus

rhythm with resting HR ≥70 bpm and either are on maximally tolerated

doses of beta-blockers or have a contraindication to beta-blocker use.

Dosage

Start with 5 mg BID. After 2 weeks of treatment, adjust dose based on

HR. Max is 7.5 mg BID. In patients with conduction defects or in whom

bradycardia could lead to hemodynamic compromise, start with 2.5 mg

twice daily.

Contraindications

Acute decompensated HF; BP <90/50 mmHg; sick sinus syndrome or

third-degree AV block, unless a functioning demand pacemaker is

present; resting HR <60 bpm prior to treatment; severe hepatic

impairment; pacemaker dependence. WARNING –fetal toxicity.

Side effects

Occurring in ≥1% of patients are bradycardia, hypertension, atrial

fibrillation, and luminous phenomena (phosphenes).

Ivabradine: Mechanism of Action▪ Inhibits the If channel

▪ Present in the cardiac SA node

▪Reduces persistently elevated

heart rate

▪Evaluated as treatment of HFrEF

who have a resting HR of at least

70 beats per minute, in sinus

rhythm, and who are also taking

the highest tolerable dose of a

beta blocker

DiFrancesco D. Curr Med Res Opin.2005;21:1115-1122.

SHIFT Study: Primary Endpoint of CV Death or

Hospitalization for Worsening HF

Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Effect of Ivabradine on

Outcomes Ivabradine

(n=3241)

Placebo (n=3264) HR p-Value

Primary endpoint 24% 29% 0.82 <0.0001

All-cause mortality 16% 17% 0.9 0.092

Death from HF 3% 5% 0.74 0.014

All-cause hospitalization 38% 42% 0.89 0.003

Any CV hospitalization 30% 34% 0.85 0.0002

CV death, hospitalization for

worsening HF, or hospitalization

for non-fatal MI

25% 30% 0.82 <0.0001

Swedberg K, et al. Lancet. 2010;376:875-885

Practice Points for Pharmacists on the Use of

Ivabradine

▪Starting dose is 5 mg twice daily (Target HR is 50-60 bpm)

▪After 2 weeks:

▪ If HR >60 bpm: Increase dose to 7.5 mg BID (Max dose)

▪If HR 50-60 bpm: Maintain initial dose

▪If HR <50 bpm or symptomatic bradycardia: Lower dose to

2.5 mg BID

▪If HR <50 bpm or symptomatic bradycardia and dose is 2.5

mg twice daily: Discontinue

Suggested Placement of New Agents

. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure. Circulation. 2016;134

Hypertension in the US

CDC/NHNS, National Health and Nutrition Examination Survey, 2011-2014. Available at www.cdc.gov Accessed 4/28/17.

Prevalence of hypertension among adults aged 18 and over, by sex and age: United States, 2011–2014

CDC/NHNS, National Health and Nutrition Examination Survey, 2011-2014. Available at www.cdc.gov Accessed 4/28/17.

Hypertension in the US

Joint National Committee (JNC)

▪Panel appointed by the National Heart,

Lung, and Blood Institute (NHLBI)

▪First guidelines (JNC-1) published in

1977

▪Subsequent updates published in 3- to 6-

year intervals

▪Last edition (JNC-8) published in 2014

2003 2014

JNC-7

ASH/ISH

JNC-8

2005 2007 2009 2011

REIN-2

ESH/ESC

AHA

ACCOMPLISH

ONTARGET

HYVET ACCORD-BP

NICE

ACCF/AHA

ESH/ESCCAMELOT

ALTITUDE

From JNC 7 to JNC 8

Development of JNC 8

▪Commissioned by the NHLBI in 2008

▪Panel members appointed

▪Developed focused critical questions relevant to practice

▪Conducted a systematic search of pertinent literature

▪Limited to randomized controlled trials (RCTs) published between 1966

and 2009

▪ Included patients age 18 or older with hypertension

▪Sample size of 100 patients or more

▪Results must have included “hard” outcomes

▪Subsequent search of studies from 2009 to 2013 required samples of

2000 or more patients

Development of JNC 8

▪In 2013, the NHLBI decides that it will no longer publish clinical

guidelines

▪Proposes to work collaboratively with other organizations

▪The appointed panel members for JNC-8 decided to publish their

findings independently

▪Published online in JAMA in 2014

▪Received no endorsements from other organizations

2014 Evidence-Based Guideline for the

Management of High Blood Pressure in Adults

Recommendation Level of

Evidence

1. General population > 60 y/o, initiate medications and treat to BP goal of

150/90 mmHg.

A

2. General population < 60 y/o, initiate medications and treat to DBP goal of

90 mmHg.

A/E

3. General population < 60 y/o, initiate medications and treat to SBP goal of

140 mmHg.

E

4. In population > 18 y/o with CKD, initiate medications and treat to BP goal

of 140/90 mmHg.

E

5. In population > 18 y/o with DM, initiate medication and treat to BP goal of

140/90 mmHg.

E

JAMA 2014;311:507-20.

Recommendation Level of

Evidence

6. In nonblack population (including DM), initial anti-hypertensive therapy

should consist of thiazide diuretic, CCB, ACE-I or ARB.

B

7. In general black population (including DM), initial anti-hypertensive

therapy should include thiazide diuretic or CCB.

C

8. In population with CKD, initial (or add-on) anti-hypertensive therapy

should include ACE-I or ARB.

B

9. Main objective of therapy is to attain and maintain a BP goal and can be

accomplished in one of two ways if not accomplished with initial therapy:

1. Increase dose of initial agent.

2. Add a second or, eventually, third agent from above list.

ACE-I and ARB should not be used in combination. Other agents may be

necessary if goal BP cannot be attained or maintained from above list.

E

2014 Evidence-Based Guideline for the

Management of High Blood Pressure in Adults

JAMA 2014;311:507-20.

Pharmacotherapy for Hypertension

▪ Randomized Controlled Trials of Intensive Versus Standard Blood Pressure

Control

ACCORD

COMPARED 2

TREATMENT GROUPS

BP < 120 vs BP 130-140

mmHg

Results: No difference in

nonfatal MIs and

strokes, and CV death

ADVANCE

Perindopril +Indapamide

achieved an average BP

of 136/73 mmHg

decreased micro and

macrovascular

complications and risk of

death

The ACCORD Study Group. N Engl J Med 2010;362:1575-85.

Hypertension Management Algorithm

JAMA. 2014;311(5):507-520.

Hypertension Management Algorithm

JAMA. 2014;311(5):507-520.

Blood Pressure Management

▪BP >120/80 mmHg to <140/90 mmHg▪Lifestyle changes

▪Weight loss if overweight

▪DASH diet

▪Increased physical activity

▪Moderate alcohol intake

▪BP>140/90 mmHg▪In addition to lifestyle therapy have prompt initiation initiation and titration of pharmacological therapy to achieve BP goals▪ If BP goal is not reached within 1 month, add another agent or increase the dose

Pharmacotherapy for Hypertension

▪ACE-Is, ARBs, CCBs or thiazides ▪Evidence-based first line drugs for patients with diabetes and HTN

▪Most patients will need two or more drugs to reach BP goals▪On Average 1 medication decreases BP by 10/5 mmHg

▪One of the medications should be taken at bedtime▪Better BP control and less adverse effects

▪Avoid using ACE-I and ARBs in combination leads to more ADE’s and renal impairment

▪Add-ons with positive outcomes include thiazide diuretics and amlodipine ▪Loop diuretic is recommended if eGFR is <30 ml/min

▪Patients receiving ACE-Is, ARBs, and/or diuretics monitor serum Cr/eGFR and potassium periodically

Monitoring Parameters for Antihypertensive

Medications

Class Adverse Effect

ACEI/ARBs Hyperkalemia, ↑ SCr, angioedema,

hypotension, cough (ACEI only)

Diuretics Hyperuricemia, electrolyte disturbances, ↑

Ca2+, hyperglycemia, hyperlipidemia

DHP CCB Peripheral edema, flushing, reflex tachycardia

Approach to Treatment

▪Focus on reduction of cardiovascular risk in 4 statin benefit

groups

▪Clinical ASCVD

▪LDL >190 mg/dL

▪Age 40-75 years + diabetes + LDL 70-189 mg/dL

▪Age 40-75 + ASCVD 10 year risk of > 7.5%

▪A new viewpoint on goals of treatment

▪Global risk assessment for primary prevention

▪Safety recommendations

Dyslipidemia Treatment

▪Lifestyle modification

▪Focus on weight loss (if indicated)

▪Reduce saturated fat, trans fat, and cholesterol intake

▪Increase omega-3 fatty acids, viscous fiber, plant sterols

▪Increase physical activity

▪Statin therapy

▪Given to ALL patients age > 40 with diabetes

▪Regardless of baseline lipid levels

ATP IV Cholesterol Targets

High-Intensity (LDL-C reduction > 50%) Moderate-Intensity (LDL-C reduction 30 –

50%)

Age < 75 years + clinical ASCVD Age > 75 years + clinical ASCVD

Age 40–75 years+ diabetes + ASCVD risk >

7.5%

Age 40–75 years+ diabetes and ASCVD risk <

7.5%

LDL-C > 190 mg/dL

ASCVD > 7.5%

AACE/ACE Lipid Targets in Patients with

T2DM

HIGH RISK (T2DM, no other

risk factors, age <40)

VERY HIGH RISK (T2DM +

ASCVD risk factors)

LDL-C (mg/dl) <100 <70

Non-HDL-C (mg/dl) <130 <100

TG (mg/dl) <150 <150

TC/HDL-C <3.5 <3.0

Apo B (mg/dl) <90 <80

LDL-P (nmol/L) <1200 <1000

Garber AJ, et al. Endocr Pract. 2016;22(1):84-113.

New Perspective on LDL-C & Non–HDL-C

• Lack of RCT evidence to support titration of drug therapy to specific

LDL-C and/or non–HDL-C goals

• Appropriate intensity of statin therapy should be used to reduce

ASCVD risk in those most likely to benefit

• Quantitative comparison of statin benefits with statin risk

• Nonstatin therapies

• Did not provide ASCVD risk reduction benefits or safety profiles

comparable to statin therapy

Statin Intensity Therapies

▪Atorvastatin 40-80 mg

▪Rosuvastatin 20-40 mg

▪Patients with ACS and

LDL>50 mg/dl who could

not tolerate high dose

statins

▪Use moderate intensity

statin and ezetimibe

▪Atorvastatin 10-20 mg

▪Rosuvastatin 5-10 mg

▪Simvastatin 20-40 mg

▪Pravastatin 40-80 mg

▪Lovastatin 40 mg

▪Fluvastatin XL 80 mg

▪Fluvastatin 40 mg Q12

▪Pitavastatin 2-4 mg

High Intensity (decrease

LDL-C>50%Moderate Intensity

(decrease LDL-C 30-<50%)

Statin Initiation Recommendations to Reduce ASCVD Risk

Statin Initiation Recommendations to Reduce ASCVD Risk

Dyslipidemia Treatment

▪Intensify Lifestyle Modification and optimize glycemic control when:▪TG >150 mg/dl and/or

▪HDL <40 mg/dl (men), <50 mg/dl (women)

▪When TG >500 mg/dl ▪Evaluate for secondary causes (alcohol, diet)

▪Consider medical therapy due to increased risk of pancreatitis

Dyslipidemia Treatment

▪Choose moderate or high intensity statin based on presence of ASCVD risk factor vs overt ASCVD

▪ASCVD risk factors include:▪ -LDL-C > 100 mg/dl

▪HTN

▪Smoking

▪Overweight/obese

▪Family history of ASCVD

▪Overt ASCVD▪Previous CV events or acute coronary syndrome

Dyslipidemia Treatment

▪How to adjust a statin?▪ Change the intensity of statin therapy based on individual response

▪Side effects/tolerability▪LDL-C levels

▪Monitoring of LDL-C levels▪ Baseline, 6 weeks after start of therapy▪ Yearly if stable (on an individual basis)▪ Adverse effects: ▪ Muscle pain, liver function tests, renal function

▪Drug interactions▪ Avoid with grapefruit juice▪ Better to be take at bedtime

▪Statins are contraindicated in pregnancy▪ If TG >500 mg/dl treat to reduce risk of acute pancreatitis with

fibrates, fish oil

Statin Safety Concerns

▪Hepatotoxicity

▪Muscle adverse effects

▪Myalgias

▪ Muscle aches, soareness, stiffness, tenderness, cramps

▪Myopathy

▪ Muscle weakness

▪Myositis

▪ Muscle inflammation; pain + CK elevation Myonecrosis +/- myoglobinuria or AKI

▪Increased blood sugar?

▪Cognitive adverse effects?

Statins and Increased Risk of T2DM

▪MOA ▪Can increase insulin resistance▪ Impair the ability of the pancrease to secrete insulin

▪Risk is dose related▪Statin group had 46% increased risk of developing DM▪Juvisync® (sitagliptin/simvastatin)

Cederberg H, et al. Diabetologia. 2015 May;58(5):1109-17.

Statins and Increased Risk of T2DM ▪Should I recommend a statin for my patient?▪If a patient may benefit from a statin start one▪The risk is usually outweighed by statins' cardiovascular benefits

▪Put the risk into a perspective▪One more case of diabetes compared to about 9 fewer

cardiovascular events for every 1000 patients on a statin/year▪Suggest pravastatin if only moderate LDL lowering is needed

and diabetes risk is a concern it might DECREASE diabetes risk

American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular Disease and Risk management.

Diabetes Care 2017; 40 (Supp 1):S75-S87.

Dyslipidemia Treatment: Combination Therapy

▪Statin + Ezetemibe may be considered▪Patients with recent ACS and LDL-C >50 mg/dl

▪Patients who cannot tolerate high-intensity statin▪Statin + Fibrate

▪ Not shown to improve ASCVD and generally not recommended

▪Except: For men with TG > 204 mg/dl and HDL-C < 34 mg/dl

▪Statin + Niacin▪Not recommended

▪Statin + PCSK9 inhibitors▪May be considered for patients at high ASCVD event risk and need

additional LDL-C lowering or are intolerant to high-intensity statin

Obesity and Cardiovascular Disease

▪Obesity increases risk for:

▪Obstructive sleep apnea (independent risk factor for T2DM)

▪ Increases insulin resistance

▪Metabolic syndrome

▪Hypertension

▪Cardiovascular disease

Bae JP, et al. J Diabetes Complications.2016; 30(2): 212-220.

Obesity Treatment

• T2DM Prevention

• With T2DM: better

glycemic control

and less medication

use

• Improvement in

urinary

incontinence,

mobility and joint

pain

• Improvement in

CVD risk factors

Previous

improvements plus:

• Improvement in

sleep apnea

• Diabetes

remission?

Previous

improvements plus:

• Improvements in

CVD mortality

and all cause

mortality

• Reduction in

cancer risk

≥5% weight loss ≥10% weight loss ≥15% weight loss

Blackburn G. Obe Res. 1995; 3(suppl 2):211s-216s. Sjostrom L, et al. J Intern Med. 2013; 273: 219-234.

Does Greater Weight Loss Equal Greater

Reduction in CVD?

▪Greater weight loss=greater reduction in CVD?▪Unclear

▪Large trial that followed patients for 13 years that sustained

6% weight loss did not have better outcomes

▪No mortality benefit

▪BP reduction, control of DM and decrease in lipids =long

term benefit

▪Do not discourage pharmacotherapy for weight loss

The Look AHEAD Research Group*. Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2

Diabetes. N Engl J Med 2013; 369:145-154

FDA Guidance for Industry: Evaluating CV Risk

for New Drugs for T2DM 2008

▪To demonstrate CV safety for new medications

▪2/3 of new phase trails should establish an independent committee

to blindly adjudicate CV endpoints

▪ CV mortality, MI, Stroke, hospitalizations for ACS

▪ Include patients in the trials with higher CV risk (advanced disease, elderly, with

renal impairment

▪ Provide meta analysis across trials

▪ Include sub group assessment (age, sex, race)

▪ Longer trial duration

Importance of Cardiovascular Health in T2DM

Patients

GeneticsEnvironmental

Choice

Adipocyte

Phenotype Shift

Core

Defect

Whole

body

Pancreas

T2DMCV

Events

1.6% annual CV events

Look AHEAD Trial

CV Events

Risk for CV events starts 10 years

before diagnosis of T2DM

Could Hypoglycemic Agents Alter the Risk of

Cardiovascular Health in T2DM Patients?

▪Metformin: UKPDS trial▪Monotherapy usage was

shown to have a lower mortality compared to sulfonylureas

▪Saxagliptin: SAVOR trial▪14000 patients followed for 2

years

▪Neutral results from a cardiovascular events standpoint

▪ Increase in heart failure

▪Alogliptin-EXAMINE trial▪High risk patients with ACS

15-90 days prior to enrollment followed x 18 months

▪CV affects were neutral

▪ Increase in heart failure

▪Sitagliptin-TECOS trial▪Stable CHD patients followed

for 5 years

▪No increase in HF

▪No benefit from cardiovascular standpoint

Scirica B, et al. N Engl J Med 2013; 369:1317-1326.

White WB, et al. N Engl J Med 2013; 369:1327-1335.

EMPA-REG Outcome Trial▪Randomized, place controlled

▪ Empagliflozin (10 mg and 35 mg) vs. placebo

▪ 42 countries, 590 sites

▪ N=7020 adults with T2DM AND established CVD

▪ BMI<45 kg/m2, eGFR >30 ml/min

▪ Those not on glucose lowering drugs (12 weeks prior to randomization) A1C 7%-9%

▪ On glucose lowering agents (12 weeks prior to randomization) A1C 7%-10%

▪ Patients were allowed to be on HTN and hyperlipidemia therapy

▪ 80% of patients were on statins

▪ 70% on ACEI

▪Primary endpoint

▪ Nonfatal stroke, CV death, nonfatal MI

▪Results

▪ Hospitalizations for Heart Failure

▪ Decreased in empagliflozin arm (P=0.02)

▪ May be due to diuretic properties of this

drug

▪ Death from any cause

▪ 32% risk reduction (P<0.001)

▪ Cumulative incidence of primary

outcome

▪ 14% risk reduction P=0.04 (superiority)

▪ Nephropathy

▪ 39% relative risk reduction

LEADER Trial▪Randomized, place controlled

▪ CV safety of Liraglutide in T2DM

▪Primary outcome

▪ Nonfatal stroke, CV death, nonfatal MI

▪N=9030 (96.8% of patients completed the trial)

▪ Inclusion criteria

▪ A1C > 7% on oral agents +/- insulin or NO treatment

▪Results

▪ Primary outcome

▪ 13% risk reduction (in nonfatal MI, nonfatal stroke, CV death) (P=01 superiority)

CV Risk Reduction: Class Effect or Agent

Specific?

▪SGLT2 Inhibitors

▪ To date only benefit see is with empagliflozin

▪ Other SGLT2 inhibitors in trials

▪ Canagliflozin and dapagliflozin

▪ 2017 standards of care recommend empagliflozin to be added to patient’s regimen

▪GLP1 agonists

▪ Elixa trial with lixisenatide showed no benefit in high risk patients

▪ Has a shorter half life may have affected mortaloity benefit

▪Did A1C affect the results?

▪ Does not seem to impact cardiovascular outcomes in trials

Zinman B, et al. N Eng J Med. 2015; 373: 2171-2128.

Case AA is a 65 YO white female who went to her PMD for a PE. Her PMH

is: T2DM 6 months, HTN for 1 year and has been struggling with her weight (205 lb, 5’2”). Her meds are: Norvasc® 5 mg

Metformin 500mg BID

Abnormal LABS 8/26/16: FPG=129mg/dl, urine albumin 35mg/24hrs,

LDL-C=135, triglycerides=105, HDL=55

BP=145/95

What intervention would you

make to her HTN therapy?

A. Start metoprolol 50mg BID

B. Start HCTZ 25mg daily

C. Start lisinopril 5mg daily

D. No intervention

What recommendation would you make to her

PMD?

(Check All That Are Correct)

A. Start ASA 81mg/day

B. Start Zocor ®

10mg HS

C. Get HbA1c value

D. Fluzone® High Dose

E. Ask about pneumococcal vaccine status