Is it time to reassess the role of myocardial metabolic modulation for the treatment of heart failure?
Is it time to reassess the role of myocardial metabolic modulation for the treatment of heart failure?
John P. Bois 0 2
Robert J. Gropler 0
0 Reprint requests: Robert J. Gropler, MD, Cardiovascular Imaging Laboratory, Division of Radiological Sciences, Mallinckrodt Institute of Radiology, Washington University School of Medicine , 510 S. Kingshighway, St. Louis, MO 63110 , USA
1 Cardiovascular Imaging Laboratory, Division of Radiological Sciences, Mallinckrodt Institute of Radiology, Washington University School of Medicine , St. Louis, MO , USA
2 Department of Cardiovascular Diseases, Mayo Clinic , Rochester, MN , USA
Under normal conditions, the heart utilizes a variety
of substrates (primarily fatty acids, glucose, and lactate)
to support overall oxidative metabolism which is the
primary engine for energy production. The biochemical
reactions that control the metabolism of these various
substrates provide dynamic and uniquely reciprocal
control of substrate flux through myocardial fatty acid
(FA) b-oxidation and glycolytic pathways as dictated by
ever-changing physiologic conditions such as the plasma
substrate environment, neurohumoral milieu, and level
of cardiac work. These acute adaptations in substrate
selection and metabolism are central to cardiac myocyte
However, in the progression of cardiac hypertrophy
to left ventricular (LV) dysfunction this flexibility in
substrate use is lost. Nearly 50 years ago, Wittels and
Spann made the seminal observation in pig heart that
systolic dysfunction, in response to aortic constriction,
was associated with a decrease in the oxidation of
palmitate, a long-chain fatty acid.1 This observation was
confirmed by numerous subsequent studies that led to
the general paradigm that the expression of genes
encoding for enzymes regulating b-oxidation are
coordinately decreased, resulting in a shift in myocardial
substrate metabolism to primarily glucose use, similar to
that seen in the fetal heart.2 These metabolic changes are
paralleled by re-expression of fetal isoforms of a variety
of contractile and calcium regulatory proteins. It should
be noted that this metabolic adaptation becomes more
complex when there is concomitant insulin resistance.3
This loss of flexibility in myocardial substrate utilization
can lead to a host of downstream effects detrimental to
myocyte health including impaired energetics and
increased oxidative stress and apoptosis.4 Metabolic
imaging studies in humans with heart failure with
reduced ejection fraction (HFrEF) have generally
confirmed these metabolic patterns.5 Because oxidation of
glucose is viewed as more efficient from an oxygen
usage perspective compared with FA b-oxidation, and
the presence of concomitant insulin resistance, there has
been tremendous interest in developing pharmacologic
therapies that stimulate myocardial glucose oxidation,
with the insulin sensitizer glucagon-like peptide-1 being
a prime example.
GLP-1 agonists are endogenous hormones with
insulinotropic and insulinomimetic effects.6 They have
been promoted for the treatment of Type-2 Diabetes
Mellitus (DM).6 However, the discovery of GLP-1
receptor mRNA in myocardial tissue as well as coronary
endothelial cells7 prompted interest in its potential
utilization in the HFrEF population. Specifically, it has
been postulated that in HFrEF the reduction in
myocardial insulin sensitivity in the setting of increased
dependence upon glucose as a substrate for metabolism
leads to energy depletion and impaired systolic function.
Consequently, restoring myocardial glucose metabolism
by GLP-1 could potentially improve myocardial
Initial animal models for the use of GLP-1 to treat
heart failure were promising. For example, canine
experiments demonstrated augmented overall
myocardial glucose utilization (MGU) and improvement
in left ventricular function after infusion of GLP-1.8
Furthermore, GLP-1 infusion was also associated with
vasodilation and increased myocardial blood flow
(MBF) with an accompanying improvement in survival.9
The mechanism behind the increased MBF was
attributed to GLP-1-induced increase in myocardial nitric
oxide production. These promising animal studies
prompted investigations of the potential therapeutic
effects of GLP-1 in humans.
Unfortunately, the use of GLP-1 in initial human
trials has not been definitive in demonstrating benefit.
For example, GLP-1 agonism augmented MGU
[measured by PET with 18F-fluorodeoxyglucose (FDG)] in
lean patients but not in obese or diabetic subjects.10
Similarly in DM patients, GLP-1 agonism has been
shown to either increase resting MBF or have no
effect.11 In non-DM patients with HFrEF (AHA class II/
III) of either ischemic or non-ischemic etiology, the
GLP-1 agonist, albiglutide, failed to increase
PETderived measurements of MGU or oxygen consumption
(using 11C-acetate) but did increase peak oxygen
Three randomized controlled trials have continued
the debate regarding the efficacy of GLP-1 agonists and
have introduced concern regarding their safety. The
LEADER trial assessed the efficacy of the GLP-1
agonist, liraglutide, in DM patients with at least one
cardiovascular risk factor.13 Compared to placebo, the
liraglutide group demonstrated a lower rate of mortality
with a trend towards less non-fatal myocardial
infarction, stroke, or hospitalization for heart failure.
Conversely, the LIVE trial assessed clinically
stable HFrEF patients with and without DM and found
no improvement in LV ejection fraction (LVEF) as well
as a higher rate of adverse events including death,
ventricular tachycardia, and heart failure exacerbation in
the liraglutide cohort.14 Similar to the LIVE trial, the
FIGHT trial examined the efficacy of liraglutide in the
HFrEF population but unlike LIVE focused on those
patients with recent heart failure exacerbations.15 A
nonsignificant trend of worse cardiovascular outcomes was
witnessed in patients receiving liraglutide.
Consequently, concern has risen regarding the safety of the use
of liraglutide in the heart failure population and the need
for fundamental studies to better understand the biologic
actions of these drugs in normal and diseased human
It is within this context that Nielsen et al.
investigated the ‘‘effect of liraglutide on myocardial glucose
uptake and blood flow in stable chronic heart failure.’’
As a substudy of LIVE, this investigation randomized 36
stable HFrEF patients (LVEF \ 45%, New York Heart
Association I to III) without DM to 24 weeks of either
liraglutide 1.8 mg daily or placebo. MGU was assessed
by PET with FDG after administration of an oral glucose
load. MBF was measured by 15OH2O PET both at rest
and during vasodilator stress induced with adenosine.
The patients were nearly all male, lean, and
predominantly had HFrEF due an ischemic origin. It should be
noted that both insulin resistance as measured by the
homeostatic model assessment (HOMA-IR) and the
level of plasma glucose control as measured by
glycosylated hemoglobin A1c (HbA1c) were at the upper
ranges of normal. MGU, MBF and myocardial flow
reserve (stress MBF/rest MBF) remained unchanged
after treatment with liraglutide therapy. This was despite
a greater decline in HbA1c and the 2-hour post-oral
glucose [measured during an oral glucose tolerance test
(OGTT)] in the liraglutide group indicating an
improvement in systemic glucose control. Of note, heart
rate increased in the liraglutide group.
The results of Nielsen and colleagues’ study, in
concert with the recent trials conducted with GLP-1
agonists encourage reflection upon our current
understanding of the myocardial metabolic shift to an
overdependence on glucose metabolism in the HFrEF
patient and how this might impact targets for therapeutic
intervention. As mentioned above, one of the most
important determinants of myocardial substrate use is
the level of plasma substrates delivered to the heart,
particularly FAs. In the current study, the impact of
liraglutide on baseline plasma FAs was not reported. We
only know that the 2-hour post-OGTT FA levels did not
change with therapy. Assuming the baseline plasma FA
levels mirrored these levels, it would not be surprising
that MGU did not change.
It is also critical to examine the specific
demographics and clinical variables of patient population
being investigated and how this might have influenced
the study results. First, an overwhelming majority (94%)
of the study population was male. Previous animal and
human studies have demonstrated a sexual dimorphism
with regard to myocardial metabolic substrate utilization
and MBF with women exhibiting a greater dependence
on FA metabolism and men on glucose use.16 Indeed,
this sexual dimorphism persists, at least for myocardial
FA metabolism in patients with HFrEF due to
non-ischemic origin.17 Age is also a critical determinant in
myocardial substrate utilization with an increasing
dependence on MGU with advancing age.18 Obesity is
another patient attribute that needs to be considered
when assessing cardiac metabolic activity. The mean
body mass index in the current study (26 to 27 kg/m2)
suggested an overweight but not obese population. PET
imaging studies in humans have noted that overweight
to obese females have increased MBF, oxygen
consumption, and FA metabolism,19 whereas obese males
demonstrated both increased FA metabolism (but to a
lesser extent than females) and a decline in MGU and
glucose oxidation.20,21 The specific etiology of HFrEF in
Nielsen et al.’s patient population may have potentially
influenced the findings as well. Three quarters of the
patients in this study were deemed to have ischemic
HFrEF. Prior work has demonstrated that even under
mild–moderate ischemic conditions myocardial FA
utilization declines and is replaced by glucose as the
primary substrate for metabolism.22 Even after
resolution of ischemia, abnormalities in myocardial substrate
metabolism may persist (e.g., ischemic memory). While
non-ischemic dilated cardiomyopathy patients exhibit a
similar metabolic pattern, it is unclear whether they will
be consistent with the extent and magnitude of changes
seen in the ischemic HFrEF population.
Finally, it should be noted that the increase in MGU
observed in the progression from myocardial
hypertrophy to LV dysfunction is not the result of an increase in
GLUT-1 or GLUT-4 upregulation but rather from a shift
of glucose oxidation via anaplerotic flux.23 This may
explain why in Nielsen et al.’s study population
decreased serum glucose and HbA1c (i.e., stimulation of
glucose uptake by non-cardiac tissue) which are
GLUT1- and GLUT-4-derived processes were noted but
increased MGU was not.
As mentioned above, in Nielsen et al.’s study, heart
rate was increased with liraglutide therapy. This finding
is consistent with the main LIVE trial as well as several
others.13 Both prior24 and contemporary25 studies have
demonstrated the importance of optimizing heart rate
control in the HFrEF population. Therefore, an increase
in heart rate without a corresponding improvement in
MGU and MBF may have been one etiology for the
worse outcomes seen in the LIVE and FIGHT trial
patients receiving liraglutide.
Contemporary knowledge of metabolic changes in
heart failure is continuing to evolve as is our
understanding of potential therapeutic agents. Indeed, the
contribution of ketone bodies and branched chain amino
acids to the pathogenesis of heart failure is just one
example.26 Among the other areas to be explored
include the assessment of MGU in the acute HFrEF
population as well as assessing whether the use of
recombinant GLP-1 agents might be more beneficial
given that its metabolites, including GLP-1 (9 to 26)
amide, may have beneficial effects that are independent
of the GLP-1 receptor agonist.27 Furthermore, given the
expanding literature that supports unique myocardial
substrate utilization based upon specific patient
demographics such as sex and age as well as clinical
situations, including body habitus, it remains to be seen
how the results of Nielsen et al.’s study may have
differed if an alternative patient population had been
assessed. Ultimately, the current literature regarding the
benefits of GLP-1 agonist therapy in the HFrEF patient
is proving disappointing and parallels the negative
outcomes with the use of other insulin-secreting or
insulinsensitizing agents such as dipeptidyl peptidase 4
inhibitors or thiazolidinediones.28 Therefore, further
investigations of alternative patient populations need to
be conducted to determine if the results of Nielsen et al.
can be applied broadly. If similar findings are
discovered, then a shift in the current approach to therapeutic
interventions in these patients may be necessary.
The authors have nothing to disclose.
1. Wittels B , Spann JF Jr. Defective lipid metabolism in the failing heart . J Clin Invest 1968 ; 47 : 1787 - 94 .
2. Razeghi P , Young ME , Cockrill TC , Frazier OH , Taegtmeyer H . Downregulation of myocardial myocyte enhancer factor 2c and myocyte enhancer factor 2c-regulated gene expression in diabetic patients with nonischemic heart failure . Circulation 2002 ; 106 : 407 - 11 .
3. Ouwens DM , Diamant M , Fodor M , Habets DD , Pelsers MM , El Hasnaoui M , Dang ZC , van den Brom CE , Vlasblom R , Rietdijk A , Boer C , Coort SL , Glatz JF , Luiken JJ . Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated cd36-mediated fatty acid uptake and esterification . Diabetologia 2007 ; 50 : 1938 - 48 .
4. Gropler RJ . Recent advances in metabolic imaging . J Nucl Cardiol 2013 ; 20 : 1147 - 72 .
5. Tuunanen H , Engblom E , Naum A , Scheinin M , Nagren K , Airaksinen J , Nuutila P , Iozzo P , Ukkonen H , Knuuti J . Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: Evidence of relationship with insulin resistance and left ventricular dysfunction . J Card Fail 2006 ; 12 : 644 - 52 .
6. Egan JM , Meneilly GS , Habener JF , Elahi D . Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state . J Clin Endocrinol Metab 2002 ; 87 : 3768 - 73 .
7. Ban K , Noyan-Ashraf MH , Hoefer J , Bolz SS , Drucker DJ , Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways . Circulation 2008 ; 117 : 2340 - 50 .
8. Nikolaidis LA , Sturzu A , Stolarski C , Elahi D , Shen YT , Shannon RP . The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy . Cardiovasc Res 2004 ; 61 : 297 - 306 .
9. Noyan-Ashraf MH , Momen MA , Ban K , Sadi AM , Zhou YQ , Riazi AM , Baggio LL , Henkelman RM , Husain M , Drucker DJ . Glp-1r agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice . Diabetes 2009 ; 58 : 975 - 83 .
10. Moberly SP , Mather KJ , Berwick ZC , Owen MK , Goodwill AG , Casalini ED , Hutchins GD , Green MA , Ng Y , Considine RV , Perry KM , Chisholm RL , Tune JD . Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus . Basic Res Cardiol 2013 ; 108 : 365 .
11. Gejl M , Sondergaard HM , Stecher C , Bibby BM , Moller N , Botker HE , Hansen SB , Gjedde A , Rungby J , Brock B . Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes . J Clin Endocrinol Metab 2012 ; 97 : E1165 - 9 .
12. Lepore JJ , Olson E , Demopoulos L , Haws T , Fang Z , Barbour AM , Fossler M , Davila-Roman VG , Russell SD , Gropler RJ . Effects of the novel long-acting glp-1 agonist, albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction . JACC Heart Fail 2016 ; 4 : 559 - 66 .
13. Marso SP , Daniels GH , Brown-Frandsen K , Kristensen P , Mann JF , Nauck MA , Nissen SE , Pocock S , Poulter NR , Ravn LS , Steinberg WM , Stockner M , Zinman B , Bergenstal RM , Buse JB , Committee LS , Investigators LT . Liraglutide and cardiovascular outcomes in type 2 diabetes . N Engl J Med 2016 ; 375 : 311 - 22 .
14. Jorsal A , Kistorp C , Holmager P , Tougaard RS , Nielsen R , Hanselmann A , Nilsson B , Moller JE , Hjort J , Rasmussen J , Boesgaard TW , Schou M , Videbaek L , Gustafsson I , Flyvbjerg A , Wiggers H , Tarnow L . Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (live)-a multicentre, double-blind, randomised, placebo-controlled trial . Eur J Heart Fail 2017 ; 19 : 69 - 77 .
15. Margulies KB , Hernandez AF , Redfield MM , Givertz MM , Oliveira GH , Cole R , Mann DL , Whellan DJ , Kiernan MS , Felker GM , McNulty SE , Anstrom KJ , Shah MR , Braunwald E , Cappola TP. Network NHFCR . Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: A randomized clinical trial . JAMA 2016 ; 316 : 500 - 8 .
16. Peterson LR , Soto PF , Herrero P , Schechtman KB , Dence C , Gropler RJ . Sex differences in myocardial oxygen and glucose metabolism . J Nucl Cardiol 2007 ; 14 : 573 - 81 .
17. Kadkhodayan A , Lin CH , Coggan AR , Kisrieva-Ware Z , Schechtman KB , Novak E , Joseph SM , Davila-Roman VG , Gropler RJ , Dence C , Peterson LR . Sex affects myocardial blood flow and fatty acid substrate metabolism in humans with nonischemic heart failure . J Nucl Cardiol 2017 ; 24 ( 4 ): 1226 - 35 .
18. Kates AM , Herrero P , Dence C , Soto P , Srinivasan M , Delano DG , Ehsani A , Gropler RJ . Impact of aging on substrate metabolism by the human heart . J Am Coll Cardiol 2003 ; 41 : 293 - 9 .
19. Peterson LR , Herrero P , Schechtman KB , Racette SB , Waggoner AD , Kisrieva-Ware Z , Dence C , Klein S , Marsala J , Meyer T , Gropler RJ . Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women . Circulation 2004 ; 109 : 2191 - 6 .
20. Peterson LR , Herrero P , Coggan AR , Kisrieva-Ware Z , Saeed I , Dence C , Koudelis D , McGill JB , Lyons MR , Novak E , DavilaRoman VG , Waggoner AD , Gropler RJ . Type 2 diabetes, obesity, and sex difference affect the fate of glucose in the human heart . Am J Physiol Heart Circ Physiol 2015 ; 308 : H1510 - 6 .
21. Peterson LR , Soto PM , Herrero P , Mohammed S , Avidan MS , Schechtman KB , Dence C , Gropler RJ . Impact of gender on the myocardial metabolic response to obesity . J Am Coll Cardiol Imaging 2008 ; 1 : 424 - 33 .
22. Lopaschuk G . Regulation of carbohydrate metabolism in ischemia and reperfusion . Am Heart J 2000 ; 139 : S115 - 9 .
23. Pound KM , Sorokina N , Ballal K , Berkich DA , Fasano M , Lanoue KF , Taegtmeyer H , O'Donnell JM , Lewandowski ED. Substrateenzyme competition attenuates upregulated anaplerotic flux through malic enzyme in hypertrophied rat heart and restores triacylglyceride content: Attenuating upregulated anaplerosis in hypertrophy . Circ Res 2009 ; 104 : 805 - 12 .
24. Doughty RN , Whalley GA , Walsh HA , Gamble GD , Lopez-Sendon J , Sharpe N , Investigators CES . Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: The capricorn echo substudy . Circulation 2004 ; 109 : 201 - 6 .
25. Swedberg K , Komajda M , Bohm M , Borer JS , Ford I , DubostBrama A , Lerebours G , Tavazzi L . Ivabradine and outcomes in chronic heart failure (shift): A randomised placebo-controlled study . Lancet 2010 ; 376 : 875 - 85 .
26. Lopaschuk GD , Ussher JR . Evolving concepts of myocardial energy metabolism: More than just fats and carbohydrates . Circ Res 2016 ; 119 : 1173 - 6 .
27. Sokos GG , Nikolaidis LA , Mankad S , Elahi D , Shannon RP . Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure . J Card Fail 2006 ; 12 : 694 - 9 .
28. Wu S , Hopper I , Skiba M , Krum H . Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: Meta-analysis of randomized clinical trials with 55,141 participants . Cardiovasc Ther 2014 ; 32 : 147 - 58 .