Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? a unifying hypothesis

Diabetes Care

Volumn 39, Issue 7, 2016, Pages 1115-1122

  Mudaliar, Sunder ^a   Alloju, Sindura ^a   Henry, Robert R ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EMPAGLIFLOZIN; KETONE; ANTIDIABETIC AGENT; BENZHYDRYL DERIVATIVE; GLUCOSE BLOOD LEVEL; GLUCOSIDE; SLC5A2 PROTEIN, HUMAN; SODIUM GLUCOSE COTRANSPORTER 2;

CARDIORENAL SYNDROME; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; CONFERENCE PAPER; DIABETIC CARDIOMYOPATHY; DISEASE ASSOCIATION; DRUG EFFICACY; ENERGY CONSUMPTION; ENERGY METABOLISM; FATTY ACID OXIDATION; GLOMERULUS FILTRATION RATE; GLUCOSE OXIDATION; GLYCEMIC CONTROL; HEART MUSCLE ISCHEMIA; HEART MUSCLE OXYGEN CONSUMPTION; HUMAN; INCIDENCE; KIDNEY DISEASE; MITOCHONDRIAL ENERGY TRANSFER; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OXIDATIVE PHOSPHORYLATION; RISK REDUCTION; SEX DIFFERENCE; SUDDEN DEATH; SURVIVAL RATE; ANTAGONISTS AND INHIBITORS; BIOLOGICAL MODEL; BLOOD; BLOOD PRESSURE; CARDIOVASCULAR DISEASES; CLINICAL TRIAL (TOPIC); DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; GLUCOSE BLOOD LEVEL; HEART; KIDNEY; METABOLISM; METHODOLOGY; MORTALITY; PATHOPHYSIOLOGY; PHYSIOLOGY; PROCEDURES; TREATMENT OUTCOME;

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; SODIUM-GLUCOSE TRANSPORTER 2; TREATMENT OUTCOME;

EID: 84975840750     PISSN: 01495992     EISSN: 19355548     Source Type: Journal    
DOI: 10.2337/dc16-0542     Document Type: Conference Paper

References (47)

1. Nathan DM. Diabetes: advances in diagnosis and treatment. JAMA 2015;314:1052-1062
2. Gerstein HC, Miller ME, Byington RP, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559
3. Dormandy JA, Charbonnel B, Eckland DJ, et al.; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macro-Vascular Events): a randomised controlled trial. Lancet 2005;366:1279-1289
4. Scirica BM, Bhatt DL, Braunwald E, et al.; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-1326
5. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128
6. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389
7. Wanner C, Lachin J, Fitchett DH, et al. Empagliflozin and cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease (Abstract). J Am Soc Nephrol 2015;26:HI-OR01
8. Muskiet MH, van Raalte DH, van Bommel E, Smits MM, Tonneijck L. Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol 2015;3: 928-929
9. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129:587-597
10. Metzger BE, Ravnikar V, Vileisis RA, Freinkel N. "Accelerated starvation" and the skipped breakfast in late normal pregnancy. Lancet 1982;1:588-592
11. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients [published correction appears in J Clin Invest 2014; 124:1868]. J Clin Invest 2014;124:499-508
12. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509-514
13. Bell DS. Heart failure: the frequent, forgotten, and often fatal complication of diabetes. Diabetes Care 2003;26:2433-2441
14. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241:2035-2038
15. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-412
16. Tomaselli GF, Zipes DP. What causes sudden death in heart failure? Circ Res 2004;95: 754-763
17. Cahill GF Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc 2003; 114:149-161
18. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007;115:3213-3223
19. Opie LH. Heart Physiology: From Cell to Circulation. Philadelphia, Lippincott-Raven Publishers, 1998, p. 43-63
20. Heinonen I, Kudomi N, Kemppainen J, et al. Myocardial blood flow and its transit time, oxygen utilization, and efficiencyofhighly endurance-trained human heart. Basic Res Cardiol 2014;109: 413
21. Singh P, McDonough AA, Thomson SC. Metabolic basis of solute transport. In Brenner & Rector's the Kidney.10th ed. Skoreck K, Chertow GM, Marsden PA, Taal MW, Yu ASL, Eds. Philadelphia, Elsevier, 2016, p. 122-143
22. Stanley WC, Recchia FA, Lopaschuk GD. Myo-cardial substrate metabolism in the normal and failing heart. Physiol Rev 2005;85:1093-1129
23. Stanley WC, Lopaschuk GD, McCormack JG. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res 1997;34: 25-33
24. Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 2000;49:677-683
25. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation 2007;116:434-448
26. Mather KJ, Hutchins GD, Perry K, et al. Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer. Am J Physiol Endocrinol Metab 2016;310:E452-E460
27. Levelt E, Rodgers CT, Clarke WT, et al. Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2diabetes mellitus. Eur Heart J.20Septem-ber 2015 [Epub ahead of print]. DOI:10.1093/eurheartj/ehv442
28. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochon-drial metabolism. Prostaglandins Leukot Essent Fatty Acids 2004;70:309-319
29. Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1-22
30. Fukao T, Lopaschuk GD, Mitchell GA. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglan-dins Leukot Essent Fatty Acids 2004;70:243-251
31. Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care 2015;38:2344-2353
32. Inagaki N, Goda M, Yokota S, Maruyama N, Iijima H. Safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus: post hoc subgroup analyses according to body mass index in a 52-week open-label study. Expert Opin Pharmacother 2015;16:1577-1591
33. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016;65:1190-1195
34. Lommi J, Kupari M, Koskinen P, et al. Blood ketone bodies in congestive heart failure. J Am Coll Cardiol 1996;28:665-672
35. Cotter DG, Schugar RC, Crawford PA. Ke-tone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 2013;304: H1060-H1076
36. Janardhan A, Chen J, Crawford PA. Altered systemic ketone body metabolism in advanced heart failure. Tex Heart Inst J 2011;38:533-538
37. Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy trans-duction. FASEB J 1995;9:651-658
38. Neugarten J, Golestaneh L. Blood oxygenation level-dependent MRI for assessment of renal oxygenation. Int J Nephrol Renovasc Dis 2014; 7:421-435
39. Klahr S, Hamm LL, Hammerman MR, Mandel LJ. Renal metabolism: integrated responses. In Handbook of Physiology. Orloff J, Berliner RW, Eds. Oxford, Oxford University Press, 1989, p. 2263-2333
40. Novikov A, Vallon V. Sodium glucose co-transporter 2 inhibition in the diabetic kidney: an update. Curr Opin Nephrol Hypertens 2016; 25:50-58
41. Körner A, Eklöf AC, Celsi G, Aperia A. Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes 1994;43:629-633
42. Layton AT, Vallon V, Edwards A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am J Physiol Renal Physiol 2015;308:F1343-F1357
43. Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol 2012;74:351-375
44. Layton AT, Vallon V, Edwards A. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am J Physiol Renal Physiol. 13 January 2016 [Epub ahead of print]. DOI:10.1152/ajprenal.00543.2015
45. Little JR, Spitzer JJ. Uptake of ketone bodies by dog kidney in vivo. Am J Physiol 1971;221: 679-683
46. Guder WG, Wagner S, Wirthensohn G. Metabolic fuels along the nephron: pathways and intracellular mechanisms of interaction. Kidney Int 1986;29:41-45
47. Stanton RC. Sodium glucose transport 2 (SGLT2) inhibition decreases glomerular hyper-filtration: is there a role for SGLT2 inhibitors in diabetic kidney disease? Circulation 2014;129: 542-544