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.