How Do SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors and GLP-1 (Glucagon-Like Peptide-1) Receptor Agonists Reduce Cardiovascular Outcomes?

Jan 31, 2020Arteriosclerosis, thrombosis, and vascular biology

How SGLT2 Inhibitors and GLP-1 Receptor Agonists May Lower Heart Disease Risk: Completed and Ongoing Mechanism Studies

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Abstract

One small trial (n=97) of SGLT2 inhibitors found a reduction in left ventricular mass.

Mechanistic trials of SGLT2 inhibitors have explored pathways related to glucose metabolism, hemodynamics, vascular and renal actions, and cardiac effects.
Participants in these trials have included individuals with cardiovascular disease, liver disease, renal impairment, obesity, and hypertension, with some having type 2 diabetes.
GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure-lowering effects, along with potential direct effects on blood vessels, heart, and kidneys.
Very few mechanisms of action for SGLT2 inhibitors or GLP-1RAs have been convincingly demonstrated so far.
SGLT2 inhibitors have been associated with a reduction in liver fat.
GLP-1RAs have not shown major cardiovascular mechanisms in completed trials, and conflicting data exist regarding their impact on infarct size.

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OBJECTIVE: There is substantial interest in how GLP-1RA (glucagon-like peptide-1 receptor agonists) and SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce cardiovascular and renal events; yet, robust mechanistic data in humans remain sparse. We conducted a narrative review of published and ongoing mechanistic clinical trials investigating the actions of SGLT2 inhibitors and GLP-1RAs to help the community appreciate the extent of ongoing work and the variety and design of such trials. Approach and Results: To date, trials investigating the mechanisms of action of SGLT2 inhibitors have focused on pathways linked to glucose metabolism and toxicity, hemodynamic/volume, vascular and renal actions, and cardiac effects, including those on myocardial energetics. The participants studied have included those with established cardiovascular disease (including coronary artery disease and heart failure), liver disease, renal impairment, obesity, and hypertension; some of these trials have enrolled patients both with and without type 2 diabetes mellitus. GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure-lowering effects, as well as possible direct vascular, cardiac, and renal effects of these agents. Very few mechanisms of action of SGLT2 inhibitors or GLP-1RAs have so far been convincingly demonstrated. One small trial (n=97) of SGLT2 inhibitors has investigated the cardiac effects of these drugs, where a small reduction in left ventricular mass was found. Data on vascular effects are limited to one trial in type 1 diabetes mellitus, which suggests some beneficial actions. SGLT2 inhibitors have been shown to reduce liver fat. We highlight the near absence of mechanistic data to explain the beneficial effects of SGLT2 inhibitors in patients without diabetes mellitus. GLP-1RAs have not been found to have major cardiovascular mechanisms of action in the limited, completed trials. Conflicting data around the impact on infarct size have been reported. No effect on left ventricular ejection fraction has been demonstrated.

CONCLUSIONS: We have tabulated the extensive ongoing mechanistic trials that will report over the coming years. We report 2 exemplar ongoing mechanistic trials in detail to give examples of the designs and techniques employed. The results of these many ongoing trials should help us understand how SGLT2 inhibitors and GLP-1RAs improve cardiovascular and renal outcomes and may also identify unexpected mechanisms suggesting novel therapeutic applications.

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How Do SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors and GLP-1 (Glucagon-Like Peptide-1) Receptor Agonists Reduce Cardiovascular Outcomes?

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