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Empagliflozin’s Fuel Hypothesis: Not so Soon

2016; Cell Press; Volume: 24; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2016.07.018

1932-7420

Gary D. Lopaschuk, Subodh Verma,

Metabolism, Diabetes, and Cancer

The EMPA-REG OUTCOME trial (Zinman et al., 2015Zinman B. Wanner C. Lachin J.M. Fitchett D. Bluhmki E. Hantel S. Mattheus M. Devins T. Johansen O.E. Woerle H.J. et al.EMPA-REG OUTCOME InvestigatorsN. Engl. J. Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7149) Google Scholar) established cardioprotective effects of empagliflozin in high-risk diabetic patients, but the underlying mechanisms remain elusive. A recent hypothesis proposed that increased ketone oxidation contributed to the effect, but several caveats indicate that the role of myocardial ketone oxidation is far from clear. The EMPA-REG OUTCOME trial (Zinman et al., 2015Zinman B. Wanner C. Lachin J.M. Fitchett D. Bluhmki E. Hantel S. Mattheus M. Devins T. Johansen O.E. Woerle H.J. et al.EMPA-REG OUTCOME InvestigatorsN. Engl. J. Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7149) Google Scholar) established cardioprotective effects of empagliflozin in high-risk diabetic patients, but the underlying mechanisms remain elusive. A recent hypothesis proposed that increased ketone oxidation contributed to the effect, but several caveats indicate that the role of myocardial ketone oxidation is far from clear. In 2008, the FDA issued specific guidance regarding the need for anti-hyperglycemic therapies to be evaluated for cardiovascular safety in large-scale randomized trials. The FDA's recommendations were based on a growing body of uncertainty about the cardiovascular safety and efficacy of anti-hyperglycemic therapies, largely because adequately powered studies for major adverse cardiovascular events were neither done nor required for drug approval. The DPP-4 (dipeptidyl peptidase-4) inhibitors were the first class of agents to be reported in accordance with the FDA guidance. In these trials, sitagliptin, saxagliptin, and alogliptin were found to be safe in high-risk patients with diabetes; however, they did not demonstrate any superiority with respect to major adverse cardiovascular events. The question therefore arose as to if there will ever be a glucose-lowering strategy that might directly or indirectly reduce cardiovascular events beyond optimal medical therapy. This question was recently answered with the publication of the EMPA-REG OUTCOME trial (Zinman et al., 2015Zinman B. Wanner C. Lachin J.M. Fitchett D. Bluhmki E. Hantel S. Mattheus M. Devins T. Johansen O.E. Woerle H.J. et al.EMPA-REG OUTCOME InvestigatorsN. Engl. J. Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7149) Google Scholar). Like the previous trials, the EMPA-REG OUTCOME trial was an FDA-mandated safety study of the SGLT2 inhibitor empagliflozin in high-risk patients with diabetes and established cardiovascular disease. Over a period of 3 years of treatment, there was an unprecedented ∼35%–40% relative reduction in cardiovascular death and all causes of mortality; these benefits were seen regardless of the dose of empagliflozin used and across low and high eGFRs (estimated glomerular filtration rates). Importantly, the benefits were seen on top of best optimal secondary prevention strategies. As expected, the profound and precocious cardioprotective effects of empagliflozin noted in the EMPA-REG OUTCOME trial (Zinman et al., 2015Zinman B. Wanner C. Lachin J.M. Fitchett D. Bluhmki E. Hantel S. Mattheus M. Devins T. Johansen O.E. Woerle H.J. et al.EMPA-REG OUTCOME InvestigatorsN. Engl. J. Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7149) Google Scholar) have generated tremendous global excitement; however, the mechanism(s) responsible for these benefits remain entirely elusive (Sattar et al., 2016Sattar N. McLaren J. Kristensen S.L. Preiss D. McMurray J.J. Diabetologia. 2016; 59: 1333-1339Crossref PubMed Scopus (235) Google Scholar). It is proposed that the reduction in mortality is likely secondary to a reduction in heart-failure-related deaths, since hospitalization for heart failure was reduced by ∼35% with no significant effect on vascular event rates such as myocardial infarction or stroke. In addition to the diuretic hypothesis, which suggests that empagliflozin may optimize myocardial filling conditions by reducing preload and afterload, recently, a second hypothesis, namely the myocardial fuel/energetics hypothesis, has gained widespread interest. It has been hypothesized that empagliflozin may optimize cardiac energy metabolism, and that by improving myocardial energetics and substrate efficiency, empagliflozin may reduce cardiac failure (the "fuel hypothesis") (Ferrannini et al., 2016Ferrannini E. Mark M. Mayoux E. Diabetes Care. 2016; 39: 1108-1114Crossref PubMed Scopus (681) Google Scholar, Mudaliar et al., 2016Mudaliar S. Alloju S. Henry R.R. Diabetes Care. 2016; 39: 1115-1122Crossref PubMed Scopus (434) Google Scholar). Interestingly, in addition to decreasing blood glucose levels, SGLT2 inhibitors also increase blood β-hydroxybutyrate (βOHB) levels (Tahara et al., 2014Tahara A. Kurosaki E. Yokono M. Yamajuku D. Kihara R. Hayashizaki Y. Takasu T. Imamura M. Li Q. Tomiyama H. et al.J. Pharm. Pharmacol. 2014; 66: 975-987Crossref PubMed Scopus (98) Google Scholar). It has been suggested that this increase in circulating levels of βOHB offers significant cardioprotection to high-risk patients with diabetes (Ferrannini et al., 2016Ferrannini E. Mark M. Mayoux E. Diabetes Care. 2016; 39: 1108-1114Crossref PubMed Scopus (681) Google Scholar, Mudaliar et al., 2016Mudaliar S. Alloju S. Henry R.R. Diabetes Care. 2016; 39: 1115-1122Crossref PubMed Scopus (434) Google Scholar). The concept is that βOHB is a "superfuel" that is oxidized by the heart in preference to fatty acids and glucose, and that ketones not only improve cardiac function in the failing heart, but also increase mechanical efficiency. While this is an interesting postulate, several caveats regarding myocardial metabolism must be considered. First, ketone body oxidation is already increased in the failing heart (Aubert et al., 2016Aubert G. Martin O.J. Horton J.L. Lai L. Vega R.B. Leone T.C. Koves T. Gardell S.J. Krüger M. Hoppel C.L. et al.Circulation. 2016; 133: 698-705PubMed Google Scholar). Whether this is an adaptive or maladaptive process is unclear. While increased ketone oxidation may maintain fuel supply for oxidative metabolism, chronic elevations in ketone oxidation have the potential to be maladaptive. Mitochondrial protein acetylation (which compromises cardiac energetics) is increased in the failing heart, which may be due to increased acetyl-CoA supply from ketone oxidation (Horton et al., 2016Horton J.L. Martin O.J. Lai L. Riley N.M. Richards A.L. Vega R.B. Leone T.C. Pagliarini D.J. Muoio D.M. Bedi Jr., K.C. et al.JCI Insight. 2016; 2 (Published online February 25, 2016)https://doi.org/10.1172/jci.insight.84897Crossref PubMed Scopus (127) Google Scholar). Ketone oxidation may also lead to a depletion of tricarboxylic acid (TCA) cycle intermediates (i.e., decreased anaplerosis), leading to a decrease in mitochondrial oxidative phosphorylation (Russell and Taegtmeyer, 1991Russell 3rd, R.R. Taegtmeyer H. J. Clin. Invest. 1991; 87: 384-390Crossref PubMed Scopus (115) Google Scholar). Therefore, enhancing βOHB oxidation in the setting of diabetes and heart failure may be potentially undesirable. Further, it is not clear why circulating βOHB levels are elevated by empaglifozin treatment. SGTL2 inhibitors increase whole-body fatty acid oxidation, and an increase in liver fatty acid oxidation may increase ketone synthesis. However, it also cannot be ruled out that SGLT2 inhibition may also decrease ketone body clearance in the body. The possibility exists that SGLT2 inhibition may actually inhibit ketone oxidation (heart and muscle), contributing to this increase in blood ketone levels. Actual determination of what effect empaglifozin treatment has on muscle ketone oxidation rates is needed to unequivocally determine this. Of note, ketones have been touted as a "superfuel" that increases cardiac efficiency (Ferrannini et al., 2016Ferrannini E. Mark M. Mayoux E. Diabetes Care. 2016; 39: 1108-1114Crossref PubMed Scopus (681) Google Scholar, Mudaliar et al., 2016Mudaliar S. Alloju S. Henry R.R. Diabetes Care. 2016; 39: 1115-1122Crossref PubMed Scopus (434) Google Scholar). While combustion of βOHB does provide more energy per two carbon moiety than glucose or pyruvate, it actually produces less than that obtained from long-chain fatty acids. Conversely, on the basis of ATP produced per oxygen consumed (P/O ratio), metabolism of βOHB is more efficient than fatty acids but less efficient than glucose. Since fatty acids, glucose, and βOHB all compete for TCA cycle acetyl-CoA (Figure 1), increasing the metabolism of βOHB should decrease glucose oxidation, thereby potentially actually decreasing cardiac efficiency. Again, without data on rates of myocardial ketone oxidation, this postulate remains tenuous. We must also consider that in diabetes, the heart switches to a metabolic profile that includes a decrease in glucose uptake and glucose oxidation and an increase in fatty acid oxidation (Lopaschuk et al., 2010Lopaschuk G.D. Ussher J.R. Folmes C.D. Jaswal J.S. Stanley W.C. Physiol. Rev. 2010; 90: 207-258Crossref PubMed Scopus (1396) Google Scholar). In addition, in insulin resistance and diabetes, the heart also becomes insulin resistant (Zhang et al., 2013Zhang L. Jaswal J.S. Ussher J.R. Sankaralingam S. Wagg C. Zaugg M. Lopaschuk G.D. Circ Heart Fail. 2013; 6: 1039-1048Crossref PubMed Scopus (165) Google Scholar). Decreased insulin stimulation of glucose oxidation in the failing heart contributes to both an impairment of heart efficiency and the development of cardiac dysfunction (Lopaschuk et al., 2010Lopaschuk G.D. Ussher J.R. Folmes C.D. Jaswal J.S. Stanley W.C. Physiol. Rev. 2010; 90: 207-258Crossref PubMed Scopus (1396) Google Scholar). It has been proposed that ketones can compensate for defects in mitochondrial energy transduction associated with acute insulin deficiency (Ferrannini et al., 2016Ferrannini E. Mark M. Mayoux E. Diabetes Care. 2016; 39: 1108-1114Crossref PubMed Scopus (681) Google Scholar). Indeed, it has been proposed that ketones are "insulin mimetics" (Ferrannini et al., 2016Ferrannini E. Mark M. Mayoux E. Diabetes Care. 2016; 39: 1108-1114Crossref PubMed Scopus (681) Google Scholar). However, increased acetyl-CoA production from ketones has the potential to decrease acetyl-CoA production derived from glucose oxidation, thereby decreasing insulin-stimulated glucose oxidation (Figure 1). Finally, altered βOHB oxidation may also impact pro-hypertrophic pathways in the heart. βOHB is a histone deacetylase (HDAC) inhibitor, which can inhibit pro-hypertrophic transcription (Figure 1) (Shimazu et al., 2013Shimazu T. Hirschey M.D. Newman J. He W. Shirakawa K. Le Moan N. Grueter C.A. Lim H. Saunders L.R. Stevens R.D. et al.Science. 2013; 339: 211-214Crossref PubMed Scopus (995) Google Scholar). It is possible that a decrease in cardiac βOHB oxidation contributes to an increase in cardiac βOHB, which decreases HDAC activity, thereby decreasing histone acetylation. Therefore, increasing βOHB levels will inhibit HDAC and decrease hypertrophic signaling. In summary, the relationship between myocardial ketone oxidation and the cardioprotective effects of empagliflozin is far from clear. It remains unclear if empagliflozin actually increases or decreases ketone oxidation in the heart. The in vivo relationships between ketone oxidation rates and measures of cardiac structure and function in individuals with diabetes treated with and without SGLT2 inhibition are needed. For now, the fuel hypothesis is tantalizing, but, respectfully, not ready for prime time.