Evidence map›Paper›PMID 27289124›Full record

ArticleDiabetes care2016

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis.

Sunder Mudaliar, Sindura Alloju, Robert R Henry

3 registry-linked trialsAbstract read
PubMed Publisher
In one paragraph

Article in Diabetes care, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 3 registered trials, which are not on this map. Cited by 293 papers, 8 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
293citing papers in PubMed, 8 pooled it
62.4field-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 18023248PMID 15522914PMID 17556173PMID 27289126PMID 27112340PMID 27025436PMID 26861783PMID 26526662PMID 26378978PMID 25921853other papers from this trial
Open the trial in the graph
NCT03933956 phase3terminatedstarted 2020, after this paper: background citation

Metabolic Effects of the SGLT-2 Inhibitor Empagliflozin in Patients With Diabetic Nephropathy (MEDiaN)

Ran2020Enrolled2Registered outcomes3Posted comparisons0ConditionsDiabetic NephropathiesArmsempagliflozin 10 mg
PMID 24463454PMID 28395981PMID 23949796PMID 24026259PMID 27299675PMID 29142974other papers from this trial
Open the trial in the graph
NCT05719714 phase1 / phase2active not recruitingstarted 2024, after this paper: background citation

Effect of Dapagliflozin on Metabolomics and Cardiac Mechanics in Chronic Kidney Disease

Ran2024Enrolled18Registered outcomes5Posted comparisons0ConditionsChronic Kidney Diseases, Heart Failure, Heart Failure With Preserved Ejection Fraction, Kidney DiseasesArmsDapagliflozin 10 MG [Farxiga]
PMID 29166232PMID 29526832PMID 29133604PMID 27679584PMID 26981940PMID 26861783PMID 26050125PMID 25533966PMID 25370599PMID 24218128PMID 21817129PMID 21262990other papers from this trial
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3 · Its place in the literature

Who cites it

293 citing papers in PubMed, 8 syntheses or guidelines pooled it, 561 citations in OpenAlex.

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

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

3 authors at 1 institution in 1 country.

Sunder MudaliarVeterans Affairs Medical Center and University of California, San Diego School of Medicine, San Diego, CA smudaliar@vapop.ucsd.edu.
Sindura AllojuVeterans Affairs Medical Center and University of California, San Diego School of Medicine, San Diego, CA.
Robert R HenryVeterans Affairs Medical Center and University of California, San Diego School of Medicine, San Diego, CA.
University of California, San Diego · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Type 2 diabetes mellitus causes excessive morbidity and premature cardiovascular (CV) mortality. Although tight glycemic control improves microvascular complications, its effects on macrovascular complications are unclear. The recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV and all-cause mortality and hospitalization for heart failure without any effects on classic atherothrombotic events is puzzling. More puzzling is that the curves for heart failure hospitalization, renal outcomes, and CV mortality begin to separate widely within 3 months and are maintained for >3 years. Modest improvements in glycemic, lipid, or blood pressure control unlikely contributed significantly to the beneficial cardiorenal outcomes within 3 months. Other known effects of SGLT2 inhibitors on visceral adiposity, vascular endothelium, natriuresis, and neurohormonal mechanisms are also unlikely major contributors to the CV/renal benefits. We postulate that the cardiorenal benefits of empagliflozin are due to a shift in myocardial and renal fuel metabolism away from fat and glucose oxidation, which are energy inefficient in the setting of the type 2 diabetic heart and kidney, toward an energy-efficient super fuel like ketone bodies, which improve myocardial/renal work efficiency and function. Even small beneficial changes in energetics minute to minute translate into large differences in efficiency, and improved cardiorenal outcomes over weeks to months continue to be sustained. Well-planned physiologic and imaging studies need to be done to characterize fuel energetics-based mechanisms for the CV/renal benefits.

Indexed as

Sodium-Glucose Transporter 2 InhibitorsBenzhydryl CompoundsBlood GlucoseBlood PressureCardiovascular DiseasesClinical Trials as TopicDiabetes Mellitus, Type 2Energy MetabolismGlucosidesHeartHumansHypoglycemic AgentsKidneyModels, BiologicalResearch DesignSodium-Glucose Transporter 2Benzhydryl CompoundsBlood GlucoseempagliflozinGlucosidesHypoglycemic AgentsSLC5A2 protein, humanSodium-Glucose Transporter 2Sodium-Glucose Transporter 2 Inhibitors

Identifiers

PMID27289124
OpenAlexW2416348735

What Socratic holds

Textmetadata
Read underepoch 390

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 Socratic graph.