Best Care for Diabetics With Cardiovascular Disease

Norman E. Lepor, MD

Clinical Professor of Medicine

Geffen School of Medicine-UCLA

Cedars-Sinai Heart Institute

Westside Medical Associates of LA

Defining Diabetes

Diabetes and Mortality and CV

Morbidity• Seventh leading cause of death in the US in 2010

Rates of death from all causes 1.5 x then adults without

diabetes

• 71% have blood pressure > 140/90 or on hypertension therapies

• 65% of diabetics with LDL-C ≥ 140 mg/dl or on lipid medication

• Cardiovascular death rates 1.7x higher then nondiabetics

• Rate of hospitalization for acute myocardial infarction 1.8x

higher then nondiabetics

• Rate of hospitalization for stroke 1.5x higher then nondiabetics

• 60% of non-traumatic lower limb amputations in diabetics

2009–2012 National Health and Nutrition Examination Survey (NHANES),

National Center for Health Statistics, Centers for Disease Control and

Prevention.

Diabetes and Non-Cardiovascular

MorbidityIs it all about the glucose?

N Engl J Med 2011:364:829-41.

Imaging To Risk Stratify Diabetic

for Coronary Artery Disease

• Do all patients with Type II Diabetes

Mellitus have similar CV risk?

• Can imaging enhance CV risk

assessment above and beyond clinical

criteria and allow better resource

allocation based on absolute risk?

Coronary Calcium Score

• Defines presence of calcified plaque in

coronary arteries = atherosclerosis

• Does not show non-calcified plaque

• More accurate prognostic information

then Framingham Risk Score

• Once it is abnormal, no need to repeat

• Conversion rate from “0” to abnormal

is 2-4% per year

Coronary Artery Calcification

Coronary Artery Calcification: Pathophysiology, Epidemiology, Imaging Methods, and Clinical Implications, Volume: 94, Issue: 5, Pages: 1175-1192, DOI:

(10.1161/01.CIR.94.5.1175)

Coronary Artery Calcification: Pathophysiology, Epidemiology, Imaging

Methods, and Clinical Implications, Volume: 94, Issue: 5, Pages: 1175-1192,

DOI: (10.1161/01.CIR.94.5.1175)

Coronary Calcium Prevalence and

10-Year Risk in Asymptomatic Men

Example of Coronary Calcium

Score Study

Risks Associated with CCS

• Radiation exposure from the MESA trial

of 1.0 mSv

• Based on current estimates, one CCS

increases lifetime risk of radiation-

induced fatal malignancy of 0.005%

• Number needed to harm is 1 out of

20,000

Arch Int Med. 2009;169:1188-1194

Examples Of Radiation Exposure

Coronary Calcium Score and

Mortality in Diabetics

DOI: 10.2337/dc11-000 Diabetes Care 2011

Cardiovascular Event Rate for

Heinz Nixdorf Study Participants

J Am Coll Cardiol Img 2017;10:143-53

Estimated Risk and Benefit of ASA in

Primary Prevention by CCS in MESA

Study

Circ Cardiovasc Qual Outcoms 2014:7:453-60

Guideline Based Recommendations for

Coronary Calcium Scoring

Is Coronary CT Angiography Useful

in Stable Patients With Diabetics

J Am Coll Cardiol Img 2016;9:1280–8

MacDonald MR et al. Eur Heart J 2008;29:1377

CV death or HHF in patients with or without diabetes based on ejection fraction category

Diabetes is associated with a worse

prognosis in patients with heart failure

18

20

0

60

40

0 0.5 1 1.5 2 2.5 3 3.5

HFrEF: unadjusted HR 1.60

(95% CI 1.44, 1.77); p<0.0001

HFpEF: unadjusted HR 2.0

(95% CI 1.70, 2.36); p<0.0001

HFrEF

HFpEF

HFrEF

HFpEF

Cu

mu

lati

ve

in

cid

en

ce

(%

)

Follow-up (years)

No diabetesDiabetes

Residual CV Risk of in Diabetic vs

Non-Diabetics: FOURIER Study

19

Persistent Elevation of Cardiovascular Risk In

Type II Diabetics

20

MEDICAL TREATMENT TARGETS

FOR DIABETES: BEYOND GLUCOSE

• Am Heart Assoc. 2018;7:e008953. DOI: 10.1161/JAHA.118.008953

21

What Constitutes Optimal Medical

Therapy (OMT) for Diabetics With

Cardiovascular/Coronary Disease?

• To meet lipid treatment goals-moving target

High intensity statin therapy

PCSK9 inhibition

• To meet hypertension treatment goals

ACE inhibitors, Angiotensin Receptor

Blockers….

• Chronic antiplatelet therapy

Aspirin, clopidogrel, ? ticagrelor

How Are Diabetics Being MisTreated?

• Data From The PINNACLE REGISTRY

and the use of statins among

cardiologist in diabetics-38% of

diabetics not on any statin

J Am Coll Cardiol 2016;68(12):1368-9

Diabetic Pharmacology

• Landscape littered with compounds that reduce

glucose and A1C levels but no significant effect

on cardiovascular events until recently

• Could glucose be an “innocent bystander” when

it comes to cardiovascular events?

• Certainly the focus on other aspects of the

metabolic syndrome (lipids, hypertension) have

yielded benefits

Pathophysiologic Abnormalities Targeted

by Available Diabetic Medications

Ralph A. DeFronzo et al. Diabetes Spectr 2014;27:100-112

©2014 by American Diabetes Association

Metformin

• Increase the sensitivity of muscle, fat and liver to

endogenous and exogenous insulin

• Metformin has been approved for use in the

treatment of T2DM since 1959 and is today the most

widely prescribed drug for this indication

• The exact molecular mechanism of action of

metformin is debated

primary target seems to be the mitochondrion where it

accumulates and induces a reduction in ATP synthesis

leading to activation the AMP-activated protein kinase which

switches the cell from an anabolic to a catabolic state,

leading to a reduction in hepatic gluconeogenesis and

increase in glucose uptake into muscle cells.

indirectly induces the expression of insulin receptors and

tyrosine kinase activity, thereby enhancing insulin sensitivity

and reducing insulin resistance in patients

Nat Rev Endocrinol 2014; 10: 143–56.

Metformin-The Myth

• Based on subset of only 342 obese diabetic

patients in a sub study of UKPDS

• Meta-analysis of 35 clinical trials selected

including 7,171 and 11,301 participants treated

with metformin and comparator, respectively,

who had 451 and 775 cardiovascular events,

respectively.

Metformin was not associated with significant

harm or benefit on cardiovascular events (

0.94[0.82-1.07], p = 0.34)

Concomitant use with sulfonylureas was

associated with reduced survival 1.432[1.068-

1.918], p = 0.016).

Diabetes Obes Metab. 2011 Mar;13(3):221-8. doi: 10.1111/j.1463-

1326.2010.01349

TZD’s

• Increase insulin sensitivity by acting on adipose,

muscle, and liver to increase glucose utilization

and decrease glucose production

• PPAR-gamma is found predominantly in adipose

tissue, pancreatic beta-cells, vascular

endothelium, macrophages, and the central

nervous system.

• PPAR-alpha is expressed mostly in liver, heart,

skeletal muscle, and vascular walls.

• Rosiglitazone is a purely PPAR-gamma agonist

pioglitazone also exerts some PPAR-alpha

effects. This may account for the different effects

that pioglitazone and rosiglitazone have on lipids

TZD’S• Secondary prevention of macrovascular events in patients

with type 2 diabetes in the PROactive Study (PROspective

pioglitAzone Clinical Trial In macroVascular Events): a

randomised controlled trial

• Primary endpoint was the composite of all-cause mortality,

non fatal myocardial infarction (including silent myocardial

infarction), stroke, acute coronary syndrome, endovascular

or surgical intervention in the coronary or leg arteries, and

amputation above the ankle, (HR 0·90, 95% CI 0·80–1·02,

p=0·095)

• The main secondary endpoint was the composite of all-cause

mortality, non-fatal myocardial infarction, and stroke. 301

patients in the pioglitazone group and 358 in the placebo

group reached this endpoint (0·84, 0·72–0·98, p=0·027)

Lancet. 2005 Oct 8;366(9493):1279-89.

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

• SAVOR-TIMI 53 (Saxagliptin Assessment of

Vascular Outcomes Recorded in Patients with

Diabetes Mellitus-Thrombolysis in Myocardial

Infarction)

• EXAMINE (Study of Alogliptin in Subjects with

Type 2 Diabetes and Acute Coronary Syndrome)

• TECOS (Trial Evaluating Cardiovascular

Outcomes with Sitagliptin)

Minimal enhancement of endogenous incretin levels

leading to modest A1c reduction, weight neutral, reduce

triglycerides and cholesterol and CV neutral

Saxagliptin Assessment of Vascular Outcomes Recorded

in Patients with Diabetes Mellitus-Thrombolysis in

Myocardial Infarction (SAVOR-TIMI 53)

• Primary endpoint event occurred in 613 patients in the

saxagliptin group and in 609 patients in the placebo

group (7.3% and 7.2%, p=0.99 for superiority; p<0.001

for non-inferiority).

• The major secondary endpoint of a composite of

cardiovascular death, myocardial infarction, stroke,

hospitalization for unstable angina, coronary

revascularization, or heart failure occurred in 1,059

patients in the saxagliptin group and in 1,034 patients

in the placebo group (12.8% and 12.4%, p=0.66).

• More patients in the saxagliptin group than in the

placebo group were hospitalized for heart failure (3.5%

vs. 2.8%; hazard ratio [HR] 1.27; 95% CI: 1.07 to 1.51;

p=0.007).N Engl J Med. 2013 Oct 3;369(14):1317-26.

Glucagon-Like Peptide-1 Receptor

Agonist (GLP-1 RA)

• Analogs of naturally occurring incretin GLP-1

• Long half lives

• Increase in glucose dependent insulin

secretion

• Decrease in glucose dependent glucagon

secretion

• Slow gastric emptying

• Reduction of A1C levels of 0.8 to 1.5

• Liraglutide, lixsenatide and semiglutide

• Mild cardioprotection

Liraglutide Effect and Action in Diabetes: Evaluation of

Cardiovascular Outcome Results (LEADER) Study

N Engl J Med. 2016 Jun 13. [Epub ahead of print] PubMed PMID: 27295427.

CV death, non fatal MI and

stroke

LEADER TRIAL

N Engl J Med. 2016 Jun 13. [Epub ahead of print] PubMed PMID: 27295427.

Semiglutide and Cardiovascular Events

in Patients with Type 2 DM (SUSTAIN-6)

DOI:10.1056/NEJMoa1607141

Semiglutide and Cardiovascular Events

in Patients with Type 2 DM (SUSTAIN-6)

DOI:10.1056/NEJMoa1607141

Sodium-Glucose Co-transporter 2

Inhibitors

• Canagliflozin (Invokana), dapagliflozin (Farxiga)

and empagliflozin (Jardiance), Ertugliflozin

(Steglatro)

• Reduce renal glucose reabsorption and increase

glucose excretion in the urine

• Associated with reductions in body weight, fat

mass (visceral > subcutaneous) and reduction in

blood pressure

• Nominal lipid effects and moderate glucose

lowering effect

• MOA for reduction of CV events?

EMPA-REG OUTCOME TRIAL

Patients with T2DM and high cardiovascular risk

were randomly assigned to receive 10 mg or 25

mg of empagliflozin or placebo once daily

The primary composite outcome was death from

cardiovascular causes, non-fatal myocardial

infarction or non-fatal stroke

. The key secondary composite outcome was the

primary outcome plus hospitalization for unstable

angina.

A total of 7,020 patients were treated (median

observation time, 3.1 years).

N Engl J Med. 2015 Nov 26;373(22):2117-28.

EMPA-REG OUTCOME TRIAL

Patients with T2DM and high cardiovascular

risk were randomly assigned to receive 10 mg

or 25 mg of empagliflozin or placebo once

daily

The primary composite outcome was death

from cardiovascular causes, non-fatal

myocardial infarction or non-fatal stroke

. The key secondary composite outcome was

the primary outcome plus hospitalization for

unstable angina.

A total of 7,020 patients were treated (median

observation time, 3.1 years). N Engl J Med. 2015 Nov 26;373(22):2117-28.

EMPA REG OUTCOME TRIAL

N Engl J Med. 2015 Nov 26;373(22):2117-28.

N Engl J Med. 2015 Nov 26;373(22):2117-28.

EMPA-REG SUBGROUP ANALYSIS

N Engl J Med. 2015 Nov 26;373(22):2117-28.

N Engl J Med. 2015 Nov 26;373(22):2117-28.

EMPA-REG SAFETY

CANVAS TRIAL: Canagliflozin and Cardiovascular

and Renal Events in Type 2 Diabetes

N Engl J Med 2017; 377:644-657

CANVAS TRIAL

N Engl J Med 2017; 377:644-657

CVD-REAL

https://doi.org/10.1161/CIRCULATIONAHA.117.029190

Lower Risk of Heart Failure and Death in Patients Initiated on SGLT-2

Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study

CVD-REAL

https://doi.org/10.1161/CIRCULATIONAHA.117.029190

Proposed Pathways For SGLT2-

Inhibitors and CV Protection

Diab Vasc Dis Res. 2015 Mar; 12(2): 90–100

SGLT-2 Inhibition and the Diabetic

Heart Energy Expenditure

SGLT2 inhibitor empagliflozin enhances the cardiac energy pool by increasing cardiac

energy production from glucose and fatty acid oxidation, but not ketone oxidation

Is A1C A Fake Benchmark for

Cardiovascular Outcomes?Lessons from Accord Trial and the theory that lower glucose is better

NEJM 358;24 www.nejm.org june 12, 2008

Primary and Secondary Outcomes

From ACCORD Trial

NEJM 358;24 www.nejm.org june 12, 2008

Alirocumab CV Risk Reduction in

Diabetics in Odyssey Outcomes Trial

ACCORD-LIPID: Primary Outcomes of the Prespecified Subgroups: High TG (≥204 mg/dL) and

Low HDL-C (≤34 mg/dL) vs. All Others in Full Cohort

17.32%

12.37%

10.11% 10.11%

0

2

4

6

8

10

12

14

16

18

20

Simva Simva + Fen Simva Simva + Fen

Major Fatal

or Nonfatal

CV Events

High TG (>204 mg/dL and low HDL (<34 mg/dL) All others in entire cohort

31%

lower

event rate

with simva;

adjusted

P=0.057

Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; CV, cerebrovascular; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.

Elam, et al, Clin Lipidol. 2011(6):9-20; Ginsberg, et al., The ACCORD Study Group. NEJM. 2010; 362:1563-1574.

17.6% (n=941) of entire cohort 82.4% (n=4,548) of entire cohort

79

456

60

485

229

2,264

231

2,284

The benefit associated with fenofibrate treatment

was confined to the high TG/low HDL-C

subgroup, comprising <18% of ACCORD-LIPID

trial population.

%

n−d

REDUCE-IT TRIAL (icosapent ethyl)

• 8179 patients from 11 countries who were at elevated

cardiovascular risk (had a previous cardiovascular

event or diabetes with one additional risk factor) and

had triglyceride levels of 150-499 mg/dl on statin

therapy were randomized to 4 g of the pure EPA

product daily or placebo.

• Median LDL-C = 75 mg/dl and triglycerides of 216 mg/dl

• After a median follow-up of 4.9 years, there was an

approximately 25% relative risk reduction (P<.001) in

the primary endpoint of first occurrence of a major

adverse cardiovascular event (cardiovascular death,

nonfatal myocardial infarction, nonfatal stroke,

coronary revascularization, or unstable angina

requiring hospitalization) in the EPA group

Summary

• Type II diabetes mellitus is as much a

cardiovascular disease as it is an

endocrinologic disease

• To optimize survival and reduce

cardiovascular risk, there is a need to

optimize the modifiable risk factors (lipids,

hypertension, tobacco use, obesity)

• Imaging is useful to risk stratify diabetics

• Though hemoglobin A1C is a marker of CV

risk, most diabetic treatments that reduce

A1C do no reduce CV risk

Summary

• SGLT-2 inhibitors and GLP-RA’s need

to be deployed in diabetic patients with

CV disease to minimize CV risk

• Treatments such as PCSK9 inhibitors

should be available for patients not

able to get to optimal LDL-C treatment

goals with statins