Mechanistic insights regarding the role of SGLT2 inhibitors and GLP1 agonist drugs on cardiovascular disease in diabetes

https://doi.org/10.1016/j.pcad.2019.07.005Get rights and content
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Abstract

The treatment landscape for patients with established or at high risk for cardiovascular disease and type 2 diabetes mellitus has entirely changed over the past decade, with the introduction of several anti-hyperglycemic agents. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are two anti-hyperglycemic classes which have been of special interest after multiple large cardiovascular disease (CVD) outcomes studies have demonstrated superiority of these agents compared to placebo for major adverse CVD events and in some cases, hospitalization for heart failure. Despite the dramatic results of these trials, only recently have we began to understand the mechanisms underlying these CVD benefits. Here we review the underlying mechanisms which have the greatest plausibility for both of these agents including the impact of ventricular loading conditions, direct effects on cardiac structure and function, myocardial energetics and sodium/hydrogen exchange for SGLT2 inhibitors, and the anti-atherosclerotic, anti-inflammatory, and modulation of endothelial function for GLP-1 agonists.

Abbreviations

AHGA
anti-hyperglycemic agents
ASCVD
atherosclerotic cardiovascular disease
BMI
body mass index
BP
blood pressure
Bpm
beats per minute
CAD
Coronary artery disease
CV
cardiovascular
CVD
cardiovascular disease
DPP4
dipeptidyl-peptidase-4
DPP4i
dipeptidyl-peptidase-4 inhibitor
EF
ejection fraction
FDA
Food and Drug Agency
GLP-1
glucagon-like-peptide-1
HbA1c
glycosylated hemoglobin
HDL-C
high-density lipoprotein cholesterol
HF
Heart failure
HFrEF
Heart failure with reduced ejection fraction
LDL-C
low-density lipoprotein cholesterol
LV
left ventricular
LVM
left ventricular mass
LVMi
left ventricular mass indexed
MACE
major adverse cardiovascular disease event
MI
myocardial infarction
MMP
Matrix metalloproteinases
MRI
magnetic resonance imaging
NHE
Na+/H+ exchanger
NO
Nitric oxide
PPAR
peroxisome proliferator-activated receptor
SA
sinoatrial
SBP
systolic blood pressure
SDF-1
stromal cell derived factor-1
SGLT2
Sodium-glucose cotransporter 2
STEMI
ST elevation myocardial infarction
T2D
type 2 diabetes mellitus
U.S.
United States
VSMC
vascular smooth muscle cell

Keywords

SGLT2-inhibitors
GLP-1 agonists
Cardiovascular outcomes
Cardiovascular mechanisms

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Conflict of Issues/Disclosures: Dr. Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Servier and Valeant, and is also is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization.

Dr. Connelly holds a New Investigator Salary Award from the Canadian Institutes of Health Research and an Early Researcher Award from the Ontario Ministry of Research and Innovation; is listed as an inventor on a patent application by Boehringer Ingelheim on the use of dipeptidyl peptidase-4 inhibitors in heart failure; and reports receiving research grants to his institution from AstraZeneca and Boehringer Ingelheim; support for travel to scientific meetings from Boehringer Ingelheim and honoraria for speaking engagements and ad hoc participation in advisory boards from AstraZeneca, Boehringer Ingelheim and Janssen. All other authors have no relevant conflicts of interest to declare.