Evidence map›Paper›PMID 27112340›Full record

ReviewDiabetologia2016

SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms?

Naveed Sattar, James McLaren, Søren L Kristensen, David Preiss, John J McMurray

Erratum issued Registry-linked trialOpen access · hybridAbstract readReview
PubMed Full text at PMC Publisher
In one paragraph

Review in Diabetologia, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT03151343 (Effects of SGLT-2 Inhibitor on Myocardial Perfusion, Function and Metabolism in Type 2 DM Patients at High Cardiovascular Risk), which is not on this map. Cited by 113 papers, 7 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
113citing papers in PubMed, 7 pooled it
39.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03151343 phase3completedstarted 2017, after this paper: background citation

Effects of SGLT-2 Inhibitor on Myocardial Perfusion, Function and Metabolism in Type 2 DM Patients at High Cardiovascular Risk: The SIMPle Randomized Clinical Trial

Ran2017Enrolled92Registered outcomes22Posted comparisons0ConditionsType2 Diabetes MellitusArmsempagliflozin, Placebo Oral Tablet
PMID 24948511PMID 24463454PMID 26526662PMID 24176441PMID 24449227PMID 25344694PMID 25402275PMID 25616707PMID 25755288PMID 25921853PMID 27289126PMID 27289124other papers from this trial
Open the trial in the graph
3 · Its place in the literature

Who cites it

113 citing papers in PubMed, 7 syntheses or guidelines pooled it, 312 citations in OpenAlex.

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53 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

5 authors at 3 institutions in 2 countries.

Naveed SattarBHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, UK. naveed.sattar@glasgow.ac.uk.
James McLarenBHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, UK.
Søren L KristensenDepartment of Cardiology, Gentofte Hospital, Copenhagen, Denmark.
David PreissClinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
John J McMurrayBHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, UK.
University of Glasgow · GBGentofte Hospital · DKUniversity of Oxford · GB

Funding

Medical Research Council MC_U137686861
6 · The paper itself

Abstract

While the modest reduction in the primary composite outcome of myocardial infarction, stroke or cardiovascular death in the EMPA-REG Outcomes trial was welcome, the 30-40% reductions in heart failure hospitalisation (HFH) and cardiovascular and all-cause deaths in patients treated with empagliflozin were highly impressive and unexpected. In this review, we discuss briefly why cardiovascular endpoint trials for new diabetes agents are required and describe the results of the first four such trials to have reported, as a precursor to understanding why the EMPA-REG Outcomes results came as a surprise. Thereafter, we discuss potential mechanisms that could explain the EMPA-REG Outcomes results, concentrating on non-atherothrombotic effects. We suggest that the main driver of benefit may derive from the specific effects of sodium-glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes-related maladaptive renal arteriolar responses. These haemodynamic and renal effects are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction. The net result of these processes, we argue, is an improvement in cardiac systolic and diastolic function and, thereby, a lower risk of HFH and sudden cardiac death. We also discuss whether other drugs in this class are likely to show similar cardiovascular benefits. Finally, areas for future research are suggested to better understand the relevant mechanisms and to identify other groups who may benefit from SGLT2 inhibitor therapy.

Indexed as

Sodium-Glucose Transporter 2 InhibitorsAnimalsBenzhydryl CompoundsCardiovascular DiseasesDiabetes Mellitus, Type 2GlucosidesHumansHypoglycemic AgentsKidneySodium-Glucose Transporter 2Benzhydryl CompoundsempagliflozinGlucosidesHypoglycemic AgentsSodium-Glucose Transporter 2Sodium-Glucose Transporter 2 InhibitorsBlood pressureCardiovascular mortalityEmpagliflozinHaemodynamicHeart failureRenal dysfunctionReviewSodium-glucose linked transporter-2Type 2 diabetes

Identifiers

PMID27112340
PMCPMC4901113
OpenAlexW2343975335

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.