Sodium-glucose co-transporter-2 inhibitors

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Highlights

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  SGLT2i reduce cardiovascular events, especially heart failure, and protect the kidney.

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  SGLT2i behave as diuretics with a “hybrid” mechanism, lowering blood pressure.

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  The exclusive peculiarity of SGLT2i lies in the tubule-glomerular feedback activation.

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  SGLT2i are likely to become a key drug class in the hand of internists and cardiologists.

Abstract

Aims

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been proven to lead to relevant cardiovascular benefits, regardless of glycemic control function. SGLT2i have on the one hand led to reduction in cardiovascular events such as heart failure and on the other hand to renal protection. Blood pressure reduction and kidney function play a central role in these outcomes. This focused review describes the main mechanisms and clinical aspects of SGLT2i.

Data synthesis

These drugs act on the proximal renal tubule and behave as diuretics with a “hybrid” mechanism, as they can favour both natriuresis and enhanced diuresis due to an osmotic effect dependent on glycosuria, resulting in blood pressure decrease. The exclusive peculiarity of these “diuretics”, which distinguishes them from loop and thiazide diuretics, lies also in the activation of the tubule-glomerular feedback.

Conclusions

This mechanism, resulting in modulation of arterioles’ tone and renin secretion, contributes to the favorable outcomes, suggesting a wider use of SGLT2i in internal medicine, nephrology and cardiology.

Keywords

Sodium-glucose co-transporter-2 inhibitors

Diuretics

Natriuresis

Tubule-glomerular feedback

Heart failure

Cardiovascular disease

Renal protection

Abbreviations

A1AR

A1 adenosine receptor

A2AR

A2 adenosine receptor

ABPM

24-h ambulatory blood pressure monitoring

ACCORD

Action to Control Cardiovascular Risk in Diabetes

ACEi

angiotensin converting enzyme inhibitors

AKI

acute kidney injury

ANP

atrial natriuretic peptide

ARB

angiotensin II type 1 receptor blockers

ATP

adenosine triphosphate

BP

blood pressure

CKD

chronic kidney disease

CV

cardiovascular

CVD

cardiovascular disease

eGFR

estimated glomerular filtration rate

FDA

U.S. Food and Drug Administration

GFR

glomerular filtration rate

HF

heart failure

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

KCCQ

Kansas City cardiomyopathy questionnaire

NNT

number-needed-to-treat

NPRC

natriuretic peptide clearance receptor

NPs

natriuretic peptides

PRA

plasma renin activity

RAAS

renin–angiotensin–aldosterone system

RCTs

randomized clinical trials

SGLT2i

sodium-glucose co-transporter-2 inhibitors

T1DM

type 1 diabetes mellitus

T2DM

type 2 diabetes mellitus

© 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V.