Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors

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Abstract

Diabetes mellitus currently affects over 350 million patients worldwide and is associated with many deaths from cardiovascular complications. Sodium–glucose co-transporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic drugs with cardiovascular benefits beyond other antidiabetic drugs. In the EMPA-REG OUTCOME trial, empagliflozin significantly decreases the mortality rate from cardiovascular causes [38% relative risk reduction (RRR)], the mortality rate from all-causes (32% RRR) and the rate of heart failure hospitalization (35% RRR) in diabetic patients with established cardiovascular diseases. The possible mechanisms of SGLT-2 inhibitors are proposed to be systemic effects by hemodynamic and metabolic actions. However, the direct mechanisms are not fully understood. In this review, reports concerning the effects of SGLT-2 inhibitors in models of diabetic cardiomyopathy, heart failure and myocardial ischemia from in vitro, in vivo as well as clinical reports are comprehensively summarized and discussed. By current evidences, it may be concluded that the direct effects of SGLT-2 inhibitors are potentially mediated through their ability to reduce cardiac inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ionic dyshomeostasis.

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Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

Hiddo J.L. Heerspink, Bruce A. Perkins, David H. Fitchett … (2016)

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.

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Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

Jan Bolinder, Östen Ljunggren, Joel Kullberg … (2012)

Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.

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Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs

Mikhail Kosiborod, Matthew Cavender, Alex Z Fu … (2017)

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Author and article information

Contributors

Sarayut Lahnwong: sarayut.lahn@gmail.com

Siriporn C. Chattipakorn: scchattipakorn@gmail.com

Nipon Chattipakorn:

ORCID: http://orcid.org/0000-0003-3026-718X

nchattip@gmail.com

Journal

Journal ID (nlm-ta): Cardiovasc Diabetol

Journal ID (iso-abbrev): Cardiovasc Diabetol

Title: Cardiovascular Diabetology

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2840

Publication date (Electronic): 10 July 2018

Publication date PMC-release: 10 July 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 101

Affiliations

[1 ]ISNI 0000 0000 9039 7662, GRID grid.7132.7, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, , Chiang Mai University, ; Chiang Mai, Thailand

[2 ]ISNI 0000 0004 0470 0856, GRID grid.9786.0, Department of Pharmacology, Faculty of Medicine, , Khon Kaen University, ; Khon Kaen, Thailand

[3 ]ISNI 0000 0000 9039 7662, GRID grid.7132.7, Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, , Chiang Mai University, ; Chiang Mai, 50200 Thailand

[4 ]ISNI 0000 0000 9039 7662, GRID grid.7132.7, Center of Excellence in Cardiac Electrophysiology Research, , Chiang Mai University, ; Chiang Mai, 50200 Thailand

[5 ]ISNI 0000 0000 9039 7662, GRID grid.7132.7, Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, , Chiang Mai University, ; Chiang Mai, Thailand

Author information

Nipon Chattipakorn http://orcid.org/0000-0003-3026-718X

Article

Publisher ID: 745

DOI: 10.1186/s12933-018-0745-5

PMC ID: 6038192

PubMed ID: 29301528

SO-VID: d8c54720-edee-48e6-aa99-d873966be587

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 25 May 2018

Date accepted : 6 July 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004396, Thailand Research Fund;

Award ID: RTA6080003

Award Recipient : Siriporn C. Chattipakorn

Funded by: FundRef http://dx.doi.org/10.13039/501100004192, National Science and Technology Development Agency;

Award ID: Research Chair Grant

Award Recipient : Nipon Chattipakorn

Funded by: FundRef http://dx.doi.org/10.13039/501100002842, Chiang Mai University;

Award ID: Center of Excellence Award

Award Recipient : Nipon Chattipakorn

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: sodium–glucose co-transporter 2 (sglt-2) inhibitors,heart,diabetes mellitus

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: sodium–glucose co-transporter 2 (sglt-2) inhibitors, heart, diabetes mellitus

Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 83

Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs

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