Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? A unifying hypothesis
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
These hormonal changes stimulate ketogenesis and lipolysis and raise circulating ketone bodies, including beta-OH-butyrate, an efficient energy source.
“These effects stimulate ketogenesis and lipolysis and increase circulating ketone bodies among b -OH-butyrate, which is an efficient energy source in addition to glucose (Mudaliar et al., 2016).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Mudaliar et al., 2016
Cites
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504720 · Cited by 12,315 · see citing works
Stratton, I. M. (2000) · BMJ · doi:10.1136/bmj.321.7258.405 · Cited by 9,059 · see citing works
OLSSON, A. G., McMurray, J. J. V., Thorgeirsson, G., Spaulding, C. M., Slattery, J., Pyörälà, K., Færgeman, O., Wright, R. S., Berg, K. M., Wilhelmsen, L., et al. (1994) · The Lancet · Cited by 8,467 · see citing works
Effects of Intensive Glucose Lowering in Type 2 Diabetes
(2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802743 · Cited by 7,888 · see citing works
Dormandy, J. A., Charbonnel, B., Eckland, D. J., Erdmann, E., Massi-Benedetti, M., Moules, I. K., Skene, A. M., Tan, M. H., Lefèbvre, P. J., Murray, G. D., et al. (2005) · The Lancet · doi:10.1016/s0140-6736(05)67528-9 · Cited by 4,129 · see citing works
Diabetes and cardiovascular disease. The Framingham study
Kannel, W. B. (1979) · JAMA · doi:10.1001/jama.241.19.2035 · Cited by 3,958 · see citing works
Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus
Scirica, B. M., Bhatt, D. L., Braunwald, E., Steg, P. G., Davidson, J., Hirshberg, B., Ohman, P., Frederich, R., Wiviott, S. D., Hoffman, E. B., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1307684 · Cited by 3,470 · see citing works
Pedersen, T. R. (2004) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2004.08.027 · Cited by 3,098 · see citing works
Diabetes and Cardiovascular Disease: The Framingham Study
Kannel, W. B. (1979) · JAMA · doi:10.1001/jama.1979.03290450033020 · Cited by 2,936 · see citing works
Myocardial Substrate Metabolism in the Normal and Failing Heart
Stanley, W. C., Recchia, F. A., & Lopaschuk, G. D. (2005) · Physiological Reviews · doi:10.1152/physrev.00006.2004 · Cited by 2,042 · see citing works
Tuomilehto, J., Vidgrén, G., Toivanen, L., Tuomilehto-Wolf, E., Kohtamäki, K., Stengård, J., Zimmet, P., Mackay, I., Rowley, M., & Koskela, P. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92521-6 · Cited by 1,658 · see citing works
Diabetic Cardiomyopathy Revisited
Boudina, S., & Abel, E. D. (2007) · Circulation · doi:10.1161/circulationaha.106.679597 · Cited by 1,543 · see citing works
Cherney, D. Z. I., Perkins, B. A., Soleymanlou, N., Maione, M., Lai, V., Lee, A., Fagan, N. M., Woerle, H. J., Johansen, O. E., Broedl, U. C., et al. (2014) · Circulation · doi:10.1161/circulationaha.113.005081 · Cited by 1,329 · see citing works
Cahill, G. F. (2006) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.26.061505.111258 · Cited by 1,318 · see citing works
Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., Broedl, U. C., & Woerle, H.-J. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72227 · Cited by 1,134 · cited 1× · see citing works
“production partly through an increase in glucagon and decrease in insulin levels (11,12); 3) increased FFA and ketone levels with a shift in whole-body fuel metabolism toward increased dependence on fat oxidation at the expense of glucose oxidation (11); and 4) increased carbohydrate consumption in the setting of lowe…”
BackgroundFuel selection in human skeletal muscle in insulin resistance: a reexamination.
Kelley, D. E., & Mandarino, L. J. (2000) · Diabetes · doi:10.2337/diabetes.49.5.677 · Cited by 1,017 · see citing works
Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production
Merovci, A., Solis-Herrera, C., Daniele, G., Eldor, R., Fiorentino, T. V., Tripathy, D., Xiong, J., Perez, Z., Norton, L., Abdul-Ghani, M. A., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci70704 · Cited by 795 · cited 1× · see citing works
“production partly through an increase in glucagon and decrease in insulin levels (11,12); 3) increased FFA and ketone levels with a shift in whole-body fuel metabolism toward increased dependence on fat oxidation at the expense of glucose oxidation (11); and 4) increased carbohydrate consumption in the setting of lowe…”
BackgroundVeech, R. L. (2004) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2003.09.007 · Cited by 759 · see citing works
Ferrannini, E., Baldi, S., Frascerra, S., Astiarraga, B., Heise, T., Bizzotto, R., Mari, A., Pieber, T. R., & Muscelli, E. (2016) · Diabetes · doi:10.2337/db15-1356 · Cited by 713 · see citing works
What Causes Sudden Death in Heart Failure?
Tomaselli, G. F., & Zipes, D. P. (2004) · Circulation Research · doi:10.1161/01.res.0000145047.14691.db · Cited by 561 · see citing works
Metabolic Mechanisms in Heart Failure
Ashrafian, H., Frenneaux, M. P., & Opie, L. H. (2007) · Circulation · doi:10.1161/circulationaha.107.702795 · Cited by 517 · see citing works
Regulation of energy substrate metabolism in the diabetic heart
Stanley, W. (1997) · Cardiovascular Research · doi:10.1016/s0008-6363(97)00047-3 · Cited by 480 · see citing works
Insulin, ketone bodies, and mitochondrial energy transduction
Sato, K., Kashiwaya, Y., Keon, C. A., Tsuchiya, N., King, M. T., Radda, G. K., Chance, B., Clarke, K., & Veech, R. L. (1995) · The FASEB Journal · doi:10.1096/fasebj.9.8.7768357 · Cited by 455 · see citing works
Ketone body metabolism and cardiovascular disease
Cotter, D. G., Schugar, R. C., & Crawford, P. A. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00646.2012 · Cited by 444 · see citing works
Bell, D. S. H. (2003) · Diabetes Care · doi:10.2337/diacare.26.8.2433 · Cited by 401 · see citing works
Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry
Fukao, T., Lopaschuk, G. D., & Mitchell, G. A. (2004) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2003.11.001 · Cited by 395 · see citing works
Nathan, D. M. (2015) · JAMA · doi:10.1001/jama.2015.9536 · Cited by 387 · see citing works
Vallon, V., & Thomson, S. C. (2012) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020911-153333 · Cited by 376 · see citing works
Heart Physiology: From Cell to Circulation
Opie, L. H. (1998) · Cited by 339 · see citing works
HAEMOLYTIC ANAEMIA AND ACUTE RENAL DISEASE.
Braimbridge, M. V. (1965) · PubMed · Cited by 308 · see citing works
’Accelerated starvation’ and the skipped breakfast in late normal pregnancy
Metzger, B., Vileisis, R., Ravnikar, V., & Freinkel, N. (1982) · The Lancet · doi:10.1016/s0140-6736(82)91750-0 · Cited by 256 · see citing works
Blood Ketone Bodies in Congestive Heart Failure
Lommi, J., Kupari, M. M., Koskinen, P., Näveri, H., Leinonen, H., Pulkki, K. J., & Härkönen, M. (1996) · Journal of the American College of Cardiology · doi:10.1016/0735-1097(96)00214-8 · Cited by 234 · see citing works
Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport
Mudaliar, S., Polidori, D., Zambrowicz, B., & Henry, R. R. (2015) · Diabetes Care · doi:10.2337/dc15-0642 · Cited by 225 · see citing works
Self-citationCahill, G. F., & Veech, R. L. (2003) · PubMed Central · Cited by 199 · see citing works
Increased renal metabolism in diabetes. Mechanism and functional implications
Körner, A., Eklöf, A.-C., Celsi, G., & Aperia, A. (1994) · Diabetes · doi:10.2337/diab.43.5.629 · Cited by 185 · see citing works
Levelt, E., Rodgers, C. T., Clarke, W. T., Mahmod, M., Ariga, R., Francis, J. M., Liu, A., Wijesurendra, R. S., Dass, S., Sabharwal, N. K., et al. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv442 · Cited by 171 · see citing works
Metabolic fuels along the nephron: Pathways and intracellular mechanisms of interaction
Guder, W., Wagner, S., & Wirthensohn, G. (1986) · Kidney International · doi:10.1038/ki.1986.6 · Cited by 145 · see citing works
Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition
Layton, A. T., Vallon, V., & Edwards, A. (2015) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00007.2015 · Cited by 142 · see citing works
Layton, A. T., Vallon, V., & Edwards, A. (2016) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00543.2015 · Cited by 141 · see citing works
Sodium glucose cotransporter 2 inhibition in the diabetic kidney
Novikov, A., & Vallon, V. (2015) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000187 · Cited by 106 · see citing works
Understanding EMPA-REG OUTCOME
Muskiet, M. H. A., van Raalte, D. H., van Bommel, E. J. M., Smits, M. M., & Tonneijck, L. (2015) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00424-6 · Cited by 77 · see citing works
Altered systemic ketone body metabolism in advanced heart failure.
Janardhan, A. H., Chen, J., & Crawford, P. A. (2011) · Europe PMC (PubMed Central) · Cited by 71 · see citing works
Sodium Glucose Transport 2 (SGLT2) Inhibition Decreases Glomerular Hyperfiltration
Stanton, R. C. (2013) · Circulation · doi:10.1161/circulationaha.113.007071 · Cited by 57 · see citing works
Mather, K. J., Hutchins, G. D., Perry, K. M., Territo, W. L., Chisholm, R., Acton, A. J., Glick‐Wilson, B. E., Considine, R. V., Moberly, S. P., & DeGrado, T. R. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00437.2015 · Cited by 53 · see citing works
Blood oxygenation level-dependent MRI for assessment of renal oxygenation
Neugarten, J., & Golestaneh, L. (2014) · International Journal of Nephrology and Renovascular Disease · doi:10.2147/ijnrd.s42924 · Cited by 48 · see citing works
HEINONEN, I. H. A., Kudomi, N., Kemppainen, J., Kiviniemi, A. M., Noponen, T., Luotolahti, M., Luoto, P., Oikonen, V., Sipilä, H. T., Kopra, J. J., et al. (2014) · Basic Research in Cardiology · doi:10.1007/s00395-014-0413-1 · Cited by 46 · see citing works
Uptake of ketone bodies by dog kidney in vivo
Little, & Spitzer, J. J. (1971) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1971.221.3.679 · Cited by 31 · see citing works
Metabolic Basis of Solute Transport
McDonough, A. A., & Thomson, S. C. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4160-6193-9.10004-1 · Cited by 28 · see citing works
Inagaki, N., Goda, M., Yokota, S., Maruyama, N., & Iijima, H. (2015) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2015.1055250 · Cited by 23 · see citing works
Renal Metabolism: Integrated Responses
Klahr, S., Hamm, L. L., Hammerman, M. R., & Mandel, L. J. (1992) · Comprehensive physiology · doi:10.1002/cphy.cp080249 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Inzucchi, S. E., Zinman, B., Fitchett, D., Wanner, C., Ferrannini, E., Schumacher, M., Schmoor, C., Ohneberg, K., Johansen, O. E., George, J. T., et al. (2018) · Diabetes Care · doi:10.2337/dc17-1096 · Cited by 740 · see citing works
Dunlay, S. M., Givertz, M. M., Aguilar, D., Allen, L. A., Chan, M., Desai, A. S., Deswal, A., Dickson, V. V., Kosiborod, M. N., Lekavich, C. L., et al. (2019) · Circulation · doi:10.1161/cir.0000000000000691 · Cited by 639 · see citing works
Vallon, V., & Thomson, S. C. (2017) · Diabetologia · doi:10.1007/s00125-016-4157-3 · Cited by 635 · see citing works
Renoprotective effects of sodium-glucose cotransporter-2 inhibitors
Heerspink, H. J. L., Kosiborod, M., Inzucchi, S. E., & Cherney, D. Z. I. (2018) · Kidney International · doi:10.1016/j.kint.2017.12.027 · Cited by 393 · see citing works
Das, S. R., Everett, B. M., Birtcher, K. K., Brown, J. M., Cefalu, W. T., Januzzi, J. L., Kalyani, R. R., Kosiborod, M., Magwire, M. L., Morris, P. B., et al. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.09.020 · Cited by 300 · see citing works
Neuen, B. L., Ohkuma, T., Neal, B., Matthews, D. R., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Desai, M., Li, Q., Deng, H., et al. (2018) · Circulation · doi:10.1161/circulationaha.118.035901 · Cited by 257 · see citing works
Latva-Rasku, A., Honka, M.-J., Kullberg, J., Mononen, N., Lehtimäki, T., Saltevo, J., Kirjavainen, A. K., Saunavaara, V., Iozzo, P., Johansson, L., et al. (2019) · Diabetes Care · doi:10.2337/dc18-1569 · Cited by 253 · see citing works
Lai, L.-L., Vethakkan, S. R., Nik Mustapha, N. R., Mahadeva, S., & Chan, W.-K. (2020) · Digestive Diseases and Sciences · doi:10.1007/s10620-019-5477-1 · Cited by 191 · see citing works
A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors
Sen, T., & Heerspink, H. J. L. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.02.016 · Cited by 161 · see citing works
Dunlay, S. M., Givertz, M. M., Aguilar, D., Allen, L. A., Chan, M., Desai, A. S., Deswal, A., Dickson, V. V., Kosiborod, M. N., Lekavich, C. L., et al. (2019) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2019.05.007 · Cited by 145 · see citing works
Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes
Li, J., Woodward, M., Perkovic, V., Figtree, G. A., Heerspink, H. J. L., Mahaffey, K. W., de Zeeuw, D., Vercruysse, F., Shaw, W., Matthews, D. R., et al. (2020) · JACC: Heart Failure · doi:10.1016/j.jchf.2019.08.004 · Cited by 144 · see citing works
Packer, M. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvaa064 · Cited by 86 · see citing works
Lundkvist, P., Pereira, M. J., Katsogiannos, P., Sjöström, C. D., Johnsson, E., & Eriksson, J. W. (2017) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12954 · Cited by 72 · see citing works
Effects of dapagliflozin on urinary metabolites in people with type 2 diabetes
Mulder, S., Heerspink, H. J. L., Darshi, M., Kim, J. J., Laverman, G. D., Sharma, K., & Pena, M. J. (2019) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13823 · Cited by 65 · see citing works
Kitada, M., Hirai, T., & Koya, D. (2020) · Diabetology International · doi:10.1007/s13340-020-00444-8 · Cited by 19 · see citing works
- Authors
- Mudaliar, S., Alloju, S., & Henry, R. R.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Mudaliar, Sunder
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2016-06-11
- Volume
- 39
- Issue
- 7
- Pages
- 1115-1122
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- OpenAlex
- W2416348735
- Cited by
- 571
- References
- 50
- Citations by year
- 2026: 14 · 2025: 35 · 2024: 33 · 2023: 38 · 2022: 52 · 2021: 65 · 2020: 79 · 2019: 75 · 2018: 70 · 2017: 76 · 2016: 31 · 2014: 2
- FWCI
- 84.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes Care (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- empagliflozin, SGLT2 inhibitors, type 2 diabetes, EMPA-REG OUTCOME, cardiorenal outcomes, heart failure hospitalization, renal outcomes, cardiovascular mortality, ketone bodies, energy efficiency, glucose oxidation, fat oxidation
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Benzhydryl Compounds, Blood Glucose, Blood Pressure, Cardiovascular Diseases, Clinical Trials as Topic, Diabetes Mellitus, Type 2, Energy Metabolism, Glucosides, Heart, Humans, Hypoglycemic Agents, Kidney, Models, Biological, Research Design, Treatment Outcome, Sodium-Glucose Transporter 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
