Cardiovascular Outcomes of Novel

Diabetic Pharmacotherapies

Wesley Fiser, MD

November 15, 2019

Diabetes Symposium

Disclosures

None

Pathogenesis of Atherosclerosis in Diabetes

Endothelial cell dysfunction

Inflammatory cell migration into intima

Cholesterol uptake into foam cell

Smooth muscle cell migration

mediaintima and proliferate

Extracellular matrix disruption

Cholesterol crystal accumulation

Necrotic core develops

Rupture of plaque activates

coagulation cascade leading to

thrombosis and vessel occlusion

Image: Nabel and Braunwald, NEJM 2012; 366:54-63

Pathogenesis of Atherosclerosis in Diabetes

3FXanimation

Diabetes and CV Risk

• DM confers two-fold

excess risk of CV

disease, independent

of other risk factors

• Relative risk is greater

in women and onset at

younger ageEuropean Heart Journal, ehz486, https://doi.org/10.1093/eurheartj/ehz486

CV risk stratification of diabetics

• Highest risk groups >10% risk of death in 10 years:

• Known CAD

• Target end organ damage: proteinuria, renal failure

• DM duration >20 yr

• DM and 3+ risk factors

• Type 1 diabetes by age 40 with onset 1-10 yr of age

Image: healthline.com• Stress testing for asymptomatic patient with diabetes?

• Multiple studies failed to show significant reduction in event rates of non-fatal MI or

CHF

• But noninvasive ischemic evaluation may be indicated in very high risk diabetic

populations (PAD, CKD, proteinuria, high CAC score)

Treatment targets of DM with CV disease

• Hypertension

– SBP 131-135 mmHg reduced risk of all cause mortality by 13%. (< 130mmHg

confers additional stroke protection)

– Prefer ACE inhibitors or angiotensin receptor blockers if albuminuria or LVH.

• Hyperlipidemia

• Statin, statin, statin (meta analysis of 18,000 DM showed 21% reduction in incidence

of major CV event)

• PCSK-9 inhibitor, ezetimibe

• Triglycerides: statin, fibrates, omega-3 fatty acid

• LDL target vs % reduction?

Antiplatelets

Treatment targets of DM with CV disease

Other

A1c goal <7%

Smoking cessation

Physical activity >150 min/week

BMI

Heart healthy diet

Combined reduction of A1c, SBP, and

lipids decreases CV events by 75%

Novel pharmacotherapies for

diabetes and cardiovascular

outcomes

CV impact of glucose-lowering meds

• Metformin

– Compared to conventional therapy, metformin reduced MI

by 39%, coronary death by 50%, and stroke by 41% over 10.7

yrs in T2DM without prior CV disease (observational study

UKPDS)

– No randomized CV outcome trials

Dipeptidyl peptidase-4 inhibitors

Saxagliptin, alogliptin,

sitagliptin, linagliptin

Noninferiority to standard

therapy but no significant CV

benefit

Glucagon-like peptide-1 receptor agonists

Exenatide, lixisenatide, liraglutide, semaglutide, dulaglutide

Thundiparambil Azeez Sonia, Chandra P. Sharma, in Oral Delivery of Insulin, 2014

Liraglutide significantly reduced composite CV

death, nonfatal MI, stroke by 13%

Semaglutide vs placebo reduced risk of CV and

all cause death

GLP-RA agents reduce MACE by 12%

CV Benefit: once weekly injectable, long half-

life, small reduction in SBP and weight loss

Sodium-glucose co-transporter 2 inhibitors

Empagliflozin, canagliflozin, dipagliflozin

Empagliflozin vs placebo:

• Reduced CV death by 38%

• Reduced overall mortality by 32%

• Reduced CHF hospitalization by 35%

Reduce absorption of glucose in proximal tubule of kidneys to push excess

glucose into urine

Image from http://www.diabetesincontrol.com/sglt2-inhibitors-a-new-class-of-diabetes-medications/Meta-analysis: SGLT-2 class reduce CHF hospitalization,

CV death, progression CKD regardless of pre-existing CV

disease. And reduction in CV death/nonfatal MI/stroke in

DM with existing CVD.

Why do SGLT-2 inhibitors improve CV events?

“The CV benefits of SGLT2 inhibitors are mostly unrelated to the extent of glucose lowering and occur too early to be the result of weight reduction.”

European Heart Journal 2019

“…the beneficial effects achieved in these trials are more likely the result of

a reduction in HF-associated events. They could involve effects on

haemodynamic parameters, such as reduced plasma volume, direct effects

on cardiac metabolism and function, or other CV effects”

Putting it all together

• For diabetics with CVD or high risk for CVD, GLP1 and SGLT2

inhibitors should be recommended in addition to metformin

• Mortality reduction with liraglutide and empagliflozin in

patients with DM + CVD

• GLP1 reduce arteriosclerosis-related events

• SGLT2 reduce CHF-related endpoints

• Choosing most appropriate therapy for management and

reduction of CV events, should be guided by baseline CV riskEuropean Heart Journal 2019

European Heart Journal 2019

European Heart Journal 2019

European Heart Journal 2019

Resources

Nabel and Braunwald, “A Tale of Coronary Artery Disease and Myocardial Infarction” New England Journal of Medicine, January 5, 2012; 366:54-63

Cosentino et al, “2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with EASD” European Heart Journal (2019), 1-69.

Cavender et al, “SGLT-2 Inhibitors and Cardiovascular Risk” JACC vol71 (22); June 2018.