Diabetes and CVD: Case Studies on Evolving Concepts for Management Strategies

Evan Sisson, PharmD, MSHA, BCACP, CDE, FAADE

Associate Professor, VCU School of Pharmacy

Email: emsisson@vcu.edu Twitter: @EMSisson

Presenter Disclosure Information

In compliance with the accrediting board policies, the American Diabetes Association requires the following disclosure to the participants:

Evan Sisson, PharmD

Disclosed no conflict of interest.

Objectives• Upon completion of this program, the learner should be able to:• Estimate the risk of atherosclerotic cardiovascular disease (ASCVD)

for a person with diabetes based on current guidelines.• Discuss the clinical importance of diabetes-specific risk enhancers

for cardiovascular disease.• Design an appropriate treatment plan, including goals of therapy, to

reduce ASCVD risk for a patient with diabetes.• Design an appropriate treatment regimen for patients failing statin

therapy, based on current guidelines.

3

Week 1: Mr. Smith presents for evaluation…

• 59 year old man

• PMH: type 2 diabetes, hypertension, dyslipidemia

• Medications

– Metformin 1g twice daily

– Lisinopril/HCTZ 20/12.5mg daily

– Amlodipine (Norvasc) 10mg daily

• Vitals

– Ht 64”, Wt 180 pounds, BMI 30 kg/m2

– BP136/88 mmHg sitting

4

Week 1: Mr. Smith’s fasting laboratory values…

• Cholesterol 239 mg/dL

• Triglycerides 300 mg/dL

• HDL 34 mg/dL

• LDL 146mg/dL

• AST 28 IU/L

• ALT 26 IU/L

• Fasting glucose 138 mg/dL

• A1C 8.2%

• Potassium 4.4 mg/dL

• Serum creatinine 1.5 mg/dL

5

Very High-Risk of Future ASCVD EventsMajor ASCVD Events

Recent ACS (within the past 12 mo)

History of MI (other than recent ACS event listed above)

History of ischemic stroke

Symptomatic peripheral arterial disease (history of claudication with ABI <0.85, or previous revascularization or amputation)

High-Risk Conditions

Age ≥65 y

Heterozygous familial hypercholesterolemia

History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s)

Diabetes mellitus

Hypertension

Chronic Kidney Disease (CKD with eGFR 15-59 mL/min/1.73 m2)

Current smoking

Persistently elevated LDL-C (LDL-C ≥100 mg/dL) despite maximally tolerated statin therapy and ezetimibe

History of congestive Heart Failure

Very High-Risk includes history of multiple major ASCVD events, or 1 major ASCVD event + multiple high-risk conditions.

Grundy SM, et al. JACC 2018 DOI: 10.1016/j.jacc.2018.11.003.

✓

✓

?✓

ASCVD Risk for Mr. Smith…

27.3% with history of diabetes

7

Normal BP <120/80 mmHg

Elevated BP 120-129/<80 mmHg

Stage II HypertensionBP ≥140/90 mmHg

Stage I Hypertension130-139/80-89 mmHg

Promote Optimal Lifestyle

Reassess1 year

Nonpharmacological

Therapy

Reassess3-6 months

ASCVD or 10-year Risk

>10%

2 agents• >20/10 from goal• Black adults

1 agent

Reassess1 month

Reassess1 month

At goal reassess3-6 months

No

Yes

Blood Pressure (BP) Thresholds and Recommendations for Treatment and Follow-up

J Am Coll Cardiol. Sep 2017, 23976; DOI: 10.1016/j.jacc.2017.07.745

ADA 2019>160/100 mmHg

Lancet. 2002; 360;1903-1913.

Blood Pressure Control How low is “low enough”?

Comparison of ACC/AHA and ADA Blood Pressure Thresholds

and Goals for Patients with Diabetes

ACC/AHA 2017 ADA 2019

Clinical Condition(s)

BP

Threshold,

mmHg

BP Goal,

mmHg

BP

Threshold,

mmHg

BP Goal,

mmHg

ASCVD or 10-year ASCVD risk

• ACC/AHA ≥10%

• ADA ≥15%≥130/80 <130/80 ≥130/80 <130/80

No clinical CVD and 10-year

ASCVD risk

• ACC/AHA <10%

• ADA <15%

≥140/90 <130/80 ≥140/90 <140/90

ASCVD indicates atherosclerotic cardiovascular disease; BP, blood pressure; CVD, cardiovascular disease; and SBP, systolic blood pressure.

J Am Coll Cardiol. Sep 2017, 23976; DOI: 10.1016/j.jacc.2017.07.745

Diabetes Care 2019 Jan; 42(Supplement 1): S103-S123. DOI:10.2337/dc19-2010

Dose Titration or Add-on Therapy?

Adapted from Wald DS et al. Am J Med. 2009;122:290-300.

1.04 1

1.16

0.89

1.01

0.19*0.23* 0.2*

0.37*

0.22*

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Thiazide BetaBlocker

ACE-I CCB All Classes

Incr

emen

tal S

BP

Red

uct

ion

Rat

io o

f O

bse

rved

to

Exp

ecte

d A

dd

itiv

e Ef

fect

s

Adding Drug From Another Class(on average standard doses)

Doubling Dose of Same Drug (fromstandard dose to twice standarddose)

*Statistically significant

“The additional effect of combining given doses of 2 classes of drug is approximately 5 times more effective than doubling the dose of 1 drug”

11

Center Time to Goal: Baseline DemographicsVariable PPCPM

(n = 259)SC

(n = 118)p-value

Age, y 47.2 10.5 50.4 8.2 0.005Female, % 60 41 <0.001Ethnicity, %

African-AmericanCaucasianHispanicOther/Unknown

77202

1.1

83112

3.3

0.09

BMI, mg/k2 33.6 8.3 31.67.8 0.12Comorbidities, %

DiabetesCAD

167

2522

0.03<0.001

Current smoker, % 41 34 0.18

SBP, mmHg 158 18.9 168.5 26.6 <0.001

DBP, mmHg 100.7 12.1 98.6 15.4 0.07

BP measurement

technique?

Referral process?

Dixon DL, Sisson EM, Parod ED, et al. J ClinHypertens 2018 Jan;20(1):88-95.

BP

Dixon DL, Sisson EM, Parod ED, et al. J Clin Hypertens 2018 Jan;20(1):88-95.

BP

Center Time to Goal: ResultsPPCPM SC p-value

Change in SBP -24.86 -15.83 0.0005

Change in DBP -14.96 -7.54 <0.0001

# Days to Goal BP(median, 95% CI, IQR)

36(30-43, 15-95)

259(182-322, 95-357)

<0.001

# Visits to Goal BP (mean, SD)

3.3(1.6)

2.8(1.3)

0.04

% at goal at 12 months 81% 44% <0.0001

Therapeutic Inertia 27.6% 43.7% <0.0001

Dixon DL, Sisson EM, Parod ED, et al. J Clin Hypertens 2018 Jan;20(1):88-95. Okonofua EC, Simpson KN, Jesri A, et al. Hypertension. 2006;47(3):345-51.

Therapeutic Inertia = (# visits not at BP goal) – (# visits with an intervention)total # visits

BP

American Diabetes Association Dia Care 2019;42:S90-S102©2019 by American Diabetes Association

Glucose-lowering medication in type 2 diabetes: overall approach.

15

SGLT-2 Inhibitors Benefits Beyond Glycemic Control

Circulation. 2016;134:752-72

• ~ 5 mmHg systolic and 2 mmHg diastolic

• Mechanism not fully understood (plasma contraction, reduced arterial stiffness, weight loss)

Blood Pressure reduction

• Reduction in albuminuria (~30-40%)

• Proposed to occur by afferent arteriole constriction which decreases intraglomerular pressure

Renal benefits

• EMPA-REG and CANVAS trials

CV Benefits

16

Clinical Outcomes with Liraglutide

Study Design• 9340 patients with T2D and high CV risk

• Randomization

– Liraglutide: n=4672

– Placebo: n=4668

• Noninferiority: prespecified margin = 1.3 for upper bound of 95% CI for the HR of the primary endpoint

– Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke

Key Results• Median follow-up: 3.5 years

• Difference from placebo at 36 months

– A1C: −0.40% (95% CI, −0.45% to −0.34%)

– Weight: −2.3 kg (95% CI, −2.0 to −2.5 kg)

• Primary outcome: HR 0.87 (95% CI 0.78 to 0.97); P=0.01 for superiority

• Significantly lower rates of all-cause death and CV death with liraglutide

• Increased rates of gastrointestinal events in liraglutide-treated patients

LEADER

CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.

Marso SP, et al. N Engl J Med 2016; 375:311-322j. DOI: 10.1056/NEJMoa1603827

Clinical Outcomes with Semaglutide

Study Design• 3297patients with T2D and high CV risk

• Randomization

– Semaglutide: n=1648

– Placebo: n=1649

• Noninferiority study: prespecified margin = 1.8 for upper bound of 95% CI of the HR for the primary endpoint

– Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke

Key Results• Median follow-up: 2.1 years

• Difference from placebo at 104 weeks– A1C: 0.5 mg −0.7% (95% CI, −0.8% to −0.5%)

– A1C: 1 mg -1.1% % (95% CI, −1.2% to 0.9%)

– Weight: 0.5 mg dose:−2.9 kg (95% CI,

– Weight: 1 mg dose: -4.3 kg (95% CI,

• CV outcomes– Primary: HR 0.74 (0.58–0.95); P<0.001 for

noninferiority and < 0.02 for superiority

• No significant difference in death or CV death

• Increased rates of gastrointestinal events in semaglutide-treated patients

SUSTAIN-6

CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.

Marso SP, et al. N Engl J Med 2016; 375:1834-1844. DOI: 10.1056/NEJMoa1607141

2019 ADA Guidelines: Aspirin (75–162 mg/day)

Secondary Prevention

• All patients with history of ASCVD

Primary prevention

• Increased cardiovascular risk (10-year risk >10%)

• Age >50 + one additional major risk factor

– family history of premature ASCVD

– Hypertension

– Smoking

– Dyslipidemia

– CKD/albuminuria

• Not at increased risk of bleeding

– Older age (>70 years) , anemia, kidney disease

American Diabetes Association. Diabetes Care 2019 Jan; 42(Supplement 1): S103-S123.Ridker PM. N Engl J Med 2018;379:1572-1574.

ASCEND A Study of Cardiovascular Events iN Diabetes

Participants 15,480 with diabetes

Mean follow-up 7.4 years

Serious Vascular Events 12% decrease (P=0.01)

Major bleed (GI) 29% increase (P=0.003)

All cause mortality NS

Aspirin and All-Cause Mortality in 14 Primary Prevention Trials

Ridker PM. N Engl J Med 2018;379:1572-1574.

Pati

ent

Simplified Smoking Cessation Workflow in Outpatient Setting

ASK

ADVISE to quit

CONNECT/ refer to treatment

FOLLOW-UP and reassess

Medical Assistant/Nurse

Cardiology Provider

Tobacco Treatment Specialist

Primary Care Provider

Heaviness of Smoking Index1) How many cigarettes do you smoke?2) How soon after waking?

• Discuss and confirm quit plan• Prescribe medications

1) Varenicline or combination NRT2) Bupropion or single NRT3) Nortriptyline

• Discuss need for behavioral therapy

Provide behavioral therapy(face-to-face or telephone)

Confirm and reinforce adherence to quit plan

Adapted from 2018 ACC Expert Consensus Decision Pathway on Tobacco Cessation Treatment. JACC Dec 2018, 25675; DOI:10.1016/j.jacc.2018.10.027

Group Question

Which of the following is the best option for Mr. Smith’s dyslipidemia?

A. Therapeutic lifestyle change

B. Atorvastatin 40 mg daily

C. Pitavastatin 40 mg daily

D. Fluvastatin 40 mg daily

Laboratory ValuesCholesterol 239 mg/dLTriglycerides 300 mg/dLHDL 34 mg/dLLDL 104 mg/dL

?

22

2019 ADA Guidelines: Recommendations for statin and combination treatment in adults with diabetes

Age ASCVD or 10-year

ASCVD >20%

Recommended statin intensity and combination treatment

<40 years No None

Yes High

>40 years No Moderate

Yes High

• In patients with ASCVD, if LDL cholesterol ≥70 mg/dL despite maximally tolerated statin dose,

consider adding additional LDL-lowering therapy (such as ezetimibe or PCSK9 inhibitor)

American Diabetes Association. Diabetes Care 2019 Jan; 42(Supplement 1): S103-S123.

ASCVD Risk Calculation

Primary Prevention of Adults with Diabetes and LDL-C 70-189 mg/dL

Age 20-39y Age 40-75y Age >75y

Diabetes-Specific Risk Enhancers

• Long duration of diabetes

• Type 2 ≥10 years

• Type 1 ≥20 years

• Albuminuria ≥30 mcg of

albumin/mg creatinine

• eGFR <60 mL/min/1.73 m2

• Retinopathy

• Neuropathy

• ABI <0.9

Moderate-intensity Statin

High-intensity Statin

Moderate-intensity Statin

• ASCVD >20%

• Age 50-75y

• Multiple ASCVD Risk Factors

Moderate-intensity StatinIf LDL-C >70mg/dL adding

ezetimibe is reasonable to reduce LDL-C levels by 50% or more

• Already on statin therapy →

it is reasonable to continue

• Not on statin therapy →

it may be reasonable to

initiate statin therapy after a

clinician–patient discussion

of potential benefits and risks

Adapted from Grundy SM, et al. JACC 2018 DOI: 10.1016/j.jacc.2018.11.003.

Statin Dose Intensities

✓ Atorvastatin 40-80mg

✓ Rosuvastatin 20-40mg

High-intensity(LDL-C reduction ≥ 50%)

✓ Atorvastatin 10-20mg

✓ Rosuvastatin 5-10mg

✓ Simvastatin 20-40mg

✓ Pravastatin 40-80mg

✓ Lovastatin 40mg

✓ Fluvastatin 80mg

✓ Pitavastatin 2-4mg

Moderate-intensity(LDL-C reduction 30 to <50%)

Grundy SM, et al. JACC 2018 DOI: 10.1016/j.jacc.2018.11.003. 25

When should efficacy and safety be monitored?

Start Statin

26

“…initial fasting lipid panel (TC, triglycerides, HDL-C, and calculated LDL-C),followed by a second lipid panel 4 to 12 weeks after initiation of statin therapy… [then] every 3 to 12 months as clinically indicated”

ACC Expert Consensus. J Am Coll Cardiol. 2016 Jul 5;68(1):92-125

26

1,500

1,000

500

00 50 100 150 200 250

Mean = 696,217St. Dev. = 26.95N=18,661

Freq

uen

cy

LDL-C (mg/dL)

Boekholdt SM, et al. J Am Coll Cardiol. 2014;64:485-494.

• Meta-analysis of 8 RCT with statins• 38,153 subjects • 6,286 major CV events in 5,387 patients

Variability of Achieved LDL-C with High-Intensity Statin Therapy

40% did not achieve LDL-C <70 mg/dL on Atorvastatin 80 or Rosuvastatin 20 mg daily

27

Week 6: Mr. Smith’s fasting laboratory values…

• Cholesterol 184 mg/dL

• Triglycerides 273 mg/dL

• HDL 35 mg/dL

• LDL 104 mg/dL

• AST 28 IU/L

• ALT 26 IU/L

• Fasting glucose 132 mg/dL

28

Group Question

Which of the following is the best option for Mr. Smith’s dyslipidemia?

A. Increase atorvastatin to 80 mg daily

B. Add fish oil 4 grams daily

C. Add fenofibrate 145 mg daily

D. Add ezetimibe 10mg daily

Laboratory ValuesCholesterol 184 mg/dLTriglycerides 273 mg/dLHDL 35 mg/dLLDL 104 mg/dL

?

29

Risk-Enhancing Factors for Clinician–Patient Risk Discussion: Disease States

Risk-Enhancing Factors

• Family history of premature ASCVD (males, age <55 y; females, age <65 y)

• Primary hypercholesterolemia (LDL-C, 160–189 mg/dL; non–HDL-C 190–219 mg/dL)

• Metabolic syndrome (increased waist circumference, elevated triglycerides [>175 mg/dL], elevated

blood pressure, elevated glucose, and low HDL-C [<40 mg/dL in men; <50 in women mg/dL])

• Chronic kidney disease (eGFR 15–59 mL/min/1.73 m2 with or without albuminuria; not treated with

dialysis or kidney transplantation)

• Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS

• History of premature menopause (before age 40 y) and history of pregnancy-associated conditions

that increase later ASCVD risk such as preeclampsia

• High-risk race/ethnicities (e.g., South Asian ancestry)

Risk-Enhancing Factors for Clinician–Patient Risk Discussion: Lipid/Biomarkers

Risk-Enhancing Factors

• Lipid/biomarkers: Associated with increased ASCVD risk

o Primary hypertriglyceridemia, persistently ≥175 mg/dL

o Biomarkers, if measured:

▪ high-sensitivity C-reactive protein ≥2.0 mg/L

▪ Lp(a) ≥50 mg/dL

▪ Elevated apoB ≥130 mg/dL

▪ ABI <0.9

Grundy SM, et al. JACC 2018 DOI: 10.1016/j.jacc.2018.11.003.

Statin Dose-Response CurvesLDL Reduction from Baseline

Pitavastatin

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

0

10

20

30

40

50

60

0 mg 10 mg 20 mg 40 mg 80 mg

LD

L R

ed

uc

tio

n (

%)

Dose

Average LDL cholesterol reduction in patients with primary hypercholesterolemia on monotherapy based Food and Drug Administration product labeling for each compound.

Increasing risk of myositis

Pitavastatin1

mg

2 mg 4 mg

32

For all groups: maximize statin dose, assess adherence,

recommend lifestyle changes

Clinical ASCVD

Treatment goal: ≥50% LDL-C reduction (consider LDL-C <70 or non-HDL <100)

1st: ezetimibe2nd: PCSK9i

If baseline LDL ≥190, choose either ezetimibe or PCSK9i

LDL-C >190 mg/dL

Treatment goal: ≥50% LDL-C reduction (consider LDL-C <100 or non-HDL <130)

1St: Consider eitherezetimibe or PCSK9i

2nd: both ezetimibe and PCSK9i

Diabetes (Age 40-75)

1st: ezetimibe

Treatment goal: ≥50% LDL-C reduction (consider LDL-C <100 or non-HDL <130)

10-year risk ≥7.5%

Treatment goal: 30-49% LDL-C reduction (consider LDL-C <100 or non-HDL <130)

1st: ezetimibe

J Am Coll Cardiol. 2017 Oct 3;70(14):1785-1822.

Intensification of Statin Therapy

33

3 Consequences of Hypertriglyceridemia

VLDL CETP

CE

TG

HDL

CET

P

CETG

LDL SDLDL

Hepatic Lipase

FFA/TG

I love

summer...

and fries!

SDHDL

Kidney

Hepatic Lipase

Atherogenic Dyslipidemia1. TG/VLDL-C2. Small Dense (SD) LDL3. HDL-C

Adapted from Ginsberg HN. J Clin Invest. 2000;106:453‐458.

Rapid degradation

and loss of Apo A-I

Insulin Resistance

Liver

1

2

3

CE = cholesterol esterCETP = cholesterol ester transfer proteinSD = small dense

Approach to Hypertriglyceridemia

35

Moderate

Triglyceride

175-499

mg/dL

Severe

Triglyceride

>500 mg/dL

Adapted from Grundy SM, et al. JACC 2018 DOI: 10.1016/j.jacc.2018.11.003.

Bhatt DL, et al. N Engl J Med. 2019;380:11-22. doi: 10.1056/NEJMoa1812792.

Address Underlying Causes

• Lifestyle (obesity and metabolic

syndrome)

• Secondary disorders

• Diabetes mellitus

• Chronic liver disease

• Chronic kidney disease and/or

nephrotic syndrome

• Hypothyroidism

• Triglyceride-raising drugs

• oral estrogens, tamoxifen,

raloxifene, retinoids,

immunosuppressive drugs,

beta blockers, thiazide

diuretics, interferon, atypical

antipsychotic drugs, protease

inhibitors, glucocorticoids

ASCVD >7.5%

→ initiate

moderate-

intensity statin

or intensify

therapy

Prevention of Pancreatitis

Especially if fasting TG ≥1000 mg/dL

• Implement a very low-fat diet

• Avoid carbohydrates and alcohol

• Consume omega-3 fatty acids

• Add fibrate or omega-3 therapy

(avoid gemfibrozil if concurrent use

of statin, especially if CYP-3A4)

ASCVD >7.5%

→ initiate

moderate-

intensity statin

or intensify

therapy

Established CVD, or diabetes + RF

• Add Icosapent Ethyl 2 g twice daily

(REDUCE-IT)

• Add fenofibrate (ACCORD Lipid)

Comparison of REDUCE-IT and ACCORD Lipid of Patients with High TG and Low HDL-C

Bhatt DL et al. N Engl J Med 2019;380:11-22.

Elam MB et al. JAMA Cardiol. 2017;2(4):370-380. doi:10.1001/jamacardio.2016.4828

Posttrial follow-up of ACCORD LipidREDUCE-IT

Week 10: Mr. Smith complains of muscle aches

• Discomfort is primarily in his calf muscles, and worsens in the evening when he takes his daily walks.

• He does not want to continue taking this cholesterol regimen.

• He is willing to try alternatives.

37

Statin-Associated Muscle Symptoms Clinical Index

Rosen, RS, et al. J Am Coll Cardiol. 2017;70(10):1290-301.

Pharmacokinetics of Statins

Atorva Fluva Lova Pitava Prava Rosuva Simva

Lipophilic Yes Yes Yes Yes No No Yes

MetabolismHydroxylation

oxidation, CYP3A4

CYP2C9(CYP2C8-3A4

minor)CYP3A4

Glucuronidation (UGTIA3-287,

CYP2C8/9 minor)

Sulfation, hydroxylation,

oxidation

Biliary excretion (CYP2C9-2C19

minor)CYP3A4

T ½ (h) 15-30 0.5-2.3 2.9 12 1.3-2.8 19 2-3

Rosen, RS, et al. J Am Coll Cardiol. 2017;70(10):1290-301.

Options for Managing Statin-Associated Myopathy

• Treat underlying problem, if known– Hypothyroidism, vitamin D deficiency

• Switch statins– Change from lipophilic to hydrophilic

(eg. simvastatin to pravastatin)

• Alternate dosing strategies– Rosuvastatin every-other-day

• Supplement use– Co-Q10, plant sterols

• Addition of non-statin lipid-lowering therapy– Add ezetimibe, bile acid resin or PCSK-9 inhibitor

Journal of Clinical Lipidology (2014) 8, S58–S71. 41

Diabetes and CVD Elevator Speech• Determine ASCVD Risk • Lipids: Use high intensity statin unless not tolerated

• LDL >70mg/dL→ Add ezetimibe or PCSK-9 if ASCVD• TG: Address secondary cause → Add statin → Intensify

• >1000 mg/dL→ Add fibrates or fish oil• TG >500 mg/dL→ Use high intensity statin or add TG

agent• TG 150-499 mg/dL→ Use moderate or high intensity statin

• Blood Pressure: goal <130/80mmHg for most patients• Aspirin: Reserve for patients with ASCVD or high risk• Tobacco: Use cessation drugs plus counselling