Mechanism of Increased LDL (Low-Density Lipoprotein) and decreased triglycerides with SGLT2 (sodium-glucose cotransporter 2) inhibition

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 38, Issue 9, 2018, Pages 2207-2216

  Basu, Debapriya ^a   Huggins, Lesley Ann ^a   Scerbo, Diego ^a   Obunike, Joseph ^a   Mullick, Adam E ^b   Rothenberg, Paul L ^c   Di Prospero, Nicholas A ^c   Eckel, Robert H ^d   Goldberg, Ira J ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b ISIS PHARMACEUTICALS   (United States)

^c JANSSEN RESEARCH AND DEVELOPMENT   (United States)

^d UNIVERSITY OF COLORADO   (United States)

Author keywords

canagliflozin; diabetes mellitus; lipoprotein lipase; lipoproteins; triglycerides

Indexed keywords

ANGIOPOIETIN RELATED PROTEIN 4; ANTISENSE OLIGONUCLEOTIDE; APOLIPOPROTEIN B100; CANAGLIFLOZIN; CHOLESTEROL ESTER TRANSFER PROTEIN; FATTY ACID; GLUCOSE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIPOPROTEIN LIPASE; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; SODIUM GLUCOSE COTRANSPORTER 2; TRIACYLGLYCEROL; TRIACYLGLYCEROL LIPASE; VERY LOW DENSITY LIPOPROTEIN; ANGPTL4 PROTEIN, HUMAN; ANGPTL4 PROTEIN, MOUSE; MESSENGER RNA;

ADIPOSE TISSUE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CIRCULATION; CONTROLLED STUDY; DOWN REGULATION; ENZYME ACTIVITY; GENE EXPRESSION; GLUCOSE BLOOD LEVEL; HEART; HYPERLIPIDEMIA; INSULIN DEFICIENCY; LIPID DIET; LIPID METABOLISM; LIPOPROTEIN BLOOD LEVEL; LIPOPROTEIN METABOLISM; MALE; MOUSE; MOUSE MODEL; NONHUMAN; PRIORITY JOURNAL; SKELETAL MUSCLE; STREPTOZOTOCIN-INDUCED DIABETES MELLITUS; TRANSGENIC MOUSE; TRIACYLGLYCEROL BLOOD LEVEL; TURNOVER RATE; ANIMAL; BLOOD; C57BL MOUSE; CARDIAC MUSCLE; EXPERIMENTAL DIABETES MELLITUS; GENETICS; METABOLISM; PHARMACOLOGY;

ADIPOSE TISSUE; ANGIOPOIETIN-LIKE 4 PROTEIN; ANIMALS; BLOOD GLUCOSE; DIABETES MELLITUS, EXPERIMENTAL; DOWN-REGULATION; FATTY ACIDS, NONESTERIFIED; GENE EXPRESSION; LIPOPROTEINS, LDL; MALE; MICE, INBRED C57BL; MICE, TRANSGENIC; MUSCLE, SKELETAL; MYOCARDIUM; RNA, MESSENGER; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; TRIGLYCERIDES;

EID: 85055595268     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.118.311339     Document Type: Article

References (49)

1. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733-794. doi: 10.1152/physrev.00055.2009
2. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54:3427-3434.
3. Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: A novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14:782-790. doi: 10.4158/EP.14.6.782
4. Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest. 1951;30:125-129. doi: 10.1172/JCI102424
5. Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: A review. Diabetes Metab Res Rev. 2005;21:31-38. doi: 10.1002/dmrr.532
6. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987;79:1510-1515. doi: 10.1172/JCI112981
7. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128. doi: 10.1056/NEJMoa1504720
8. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099. doi: 10.1056/NEJMc1712572
9. Agrawal N, Freitas Corradi P, Gumaste N, Goldberg IJ. Triglyceride treatment in the age of cholesterol reduction. Prog Cardiovasc Dis. 2016;59:107-118. doi: 10.1016/j.pcad.2016.08.003
10. Weintraub H. Update on marine omega-3 fatty acids: Management of dyslipidemia and current omega-3 treatment options. Atherosclerosis. 2013;230:381-389. doi: 10.1016/j.atherosclerosis.2013.07.041
11. Ptaszynska A, Hardy E, Johnsson E, Parikh S, List J. Effects of dapagliflozin on cardiovascular risk factors. Postgrad Med. 2013;125:181-189. doi: 10.3810/pgm.2013.05.2667
12. Rodríguez-Gutiérrez R, Gonzalez-Saldivar G. Canagliflozin. Cleve Clin J Med. 2014;81:87-88. doi: 10.3949/ccjm.81c.02003
13. Yu T, Sungelo MJ, Goldberg IJ, Wang H, Eckel RH. Streptozotocintreated high fat fed mice: A new type 2 diabetes model used to study canagliflozin-induced alterations in lipids and lipoproteins. Horm Metab Res. 2017;49:400-406. doi: 10.1055/s-0042-110934
14. Willecke F, Scerbo D, Nagareddy P, Obunike JC, Barrett TJ, Abdillahi ML, Trent CM, Huggins LA, Fisher EA, Drosatos K, Goldberg IJ. Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice. Arterioscler Thromb Vasc Biol. 2015;35:102-110. doi: 10.1161/ATVBAHA.114.304615
15. Renard CB, Kramer F, Johansson F, Lamharzi N, Tannock LR, von Herrath MG, Chait A, Bornfeldt KE. Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. J Clin Invest. 2004;114:659-668. doi: 10.1172/JCI17867
16. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957;226:497-509.
17. Millar JS, Cromley DA, McCoy MG, Rader DJ, Billheimer JT. Determining hepatic triglyceride production in mice: Comparison of poloxamer 407 with Triton WR-1339. J Lipid Res. 2005;46:2023-2028. doi: 10.1194/jlr.D500019-JLR200
18. Hocquette JF, Graulet B, Olivecrona T. Lipoprotein lipase activity and mRNA levels in bovine tissues. Comp Biochem Physiol B Biochem Mol Biol. 1998;121:201-212.
19. Polidori D, Sha S, Mudaliar S, Ciaraldi TP, Ghosh A, Vaccaro N, Farrell K, Rothenberg P, Henry RR. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: Results of a randomized, placebo-controlled study. Diabetes Care. 2013;36:2154-2161. doi: 10.2337/dc12-2391
20. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509-514. doi: 10.1172/JCI70704
21. Sadur CN, Eckel RH. Insulin stimulation of adipose tissue lipoprotein lipase. Use of the euglycemic clamp technique. J Clin Invest. 1982;69:1119-1125.
22. Robciuc MR, Skrobuk P, Anisimov A, Olkkonen VM, Alitalo K, Eckel RH, Koistinen HA, Jauhiainen M, Ehnholm C. Angiopoietin-like 4 mediates PPAR delta effect on lipoprotein lipase-dependent fatty acid uptake but not on beta-oxidation in myotubes. PLoS One. 2012;7:e46212. doi: 10.1371/journal.pone.0046212
23. Yu X, Burgess SC, Ge H, Wong KK, Nassem RH, Garry DJ, Sherry AD, Malloy CR, Berger JP, Li C. Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart. Proc Natl Acad Sci USA. 2005;102:1767-1772. doi: 10.1073/pnas.0409564102
24. Sukonina V, Lookene A, Olivecrona T, Olivecrona G. Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue. Proc Natl Acad Sci USA. 2006;103:17450-17455. doi: 10.1073/pnas.0604026103
25. Georgiadi A, Lichtenstein L, Degenhardt T, Boekschoten MV, van Bilsen M, Desvergne B, Müller M, Kersten S. Induction of cardiac Angptl4 by dietary fatty acids is mediated by peroxisome proliferator-activated receptor beta/delta and protects against fatty acid-induced oxidative stress. Circ Res. 2010;106:1712-1721. doi: 10.1161/CIRCRESAHA.110.217380
26. Staiger H, Haas C, Machann J, Werner R, Weisser M, Schick F, Machicao F, Stefan N, Fritsche A, Häring HU. Muscle-derived angiopoietin-like protein 4 is induced by fatty acids via peroxisome proliferator-activated receptor (PPAR)-delta and is of metabolic relevance in humans. Diabetes. 2009;58:579-589. doi: 10.2337/db07-1438
27. Kuo T, Chen TC, Yan S, Foo F, Ching C, McQueen A, Wang JC. Repression of glucocorticoid-stimulated angiopoietin-like 4 gene transcription by insulin. J Lipid Res. 2014;55:919-928. doi: 10.1194/jlr.M047860
28. Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, Ramkhelawon B, Distel E, Westerterp M, Huang LS, Schmidt AM, Orchard TJ, Fisher EA, Tall AR, Goldberg IJ. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013;17:695-708. doi: 10.1016/j.cmet.2013.04.001
29. Honda Y, Imajo K, Kato T, Kessoku T, Ogawa Y, Tomeno W, Kato S, Mawatari H, Fujita K, Yoneda M, Saito S, Nakajima A. The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice. PLoS One. 2016;11:e0146337. doi: 10.1371/journal.pone.0146337
30. Jojima T, Tomotsune T, Iijima T, Akimoto K, Suzuki K, Aso Y. Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. Diabetol Metab Syndr. 2016;8:45. doi: 10.1186/s13098-016-0169-x
31. Terasaki M, Hiromura M, Mori Y, Kohashi K, Nagashima M, Kushima H, Watanabe T, Hirano T. Amelioration of hyperglycemia with a sodium-glucose cotransporter 2 inhibitor prevents macrophage-driven atherosclerosis through macrophage foam cell formation suppression in type 1 and type 2 diabetic mice. PLoS One. 2015;10:e0143396. doi: 10.1371/journal.pone.0143396
32. Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, Choi SH, Jang HC, Lee HS, Park KS, Kim YB, Lim S. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE -/- mice fed a western diet. Diabetologia. 2017;60:364-376. doi: 10.1007/s00125-016-4158-2
33. Briand F, Mayoux E, Brousseau E, Burr N, Urbain I, Costard C, Mark M, Sulpice T. Empagliflozin, via switching metabolism toward lipid utilization, moderately increases LDL cholesterol levels through reduced LDL catabolism. Diabetes. 2016;65:2032-2038. doi: 10.2337/db16-0049
34. Mandard S, Zandbergen F, Tan NS, Escher P, Patsouris D, Koenig W, Kleemann R, Bakker A, Veenman F, Wahli W, Müller M, Kersten S. The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment. J Biol Chem. 2004;279:34411-34420. doi: 10.1074/jbc.M403058200
35. Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, Gonzalez FJ, Desvergne B, Wahli W. Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem. 2000;275:28488-28493. doi: 10.1074/jbc.M004029200
36. Vakkilainen J, Steiner G, Ansquer JC, Perttunen-Nio H, Taskinen MR. Fenofibrate lowers plasma triglycerides and increases LDL particle diameter in subjects with type 2 diabetes. Diabetes Care. 2002;25:627-628.
37. Harris WS. N-3 fatty acids and serum lipoproteins: Human studies. Am J Clin Nutr. 1997;65:1645S-1654S.
38. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA. 2008;300:2142-2152. doi: 10.1001/jama.2008.621
39. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299-308. doi: 10.1001/jama.298.3.299
40. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345-1352. doi: 10.1038/ng.2795
41. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: A "Thrifty Substrate" hypothesis. Diabetes Care. 2016;39:1108-1114. doi: 10.2337/dc16-0330
42. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: Lessons learned from the EMPA-REG OUTCOME study. Diabetes Care. 2016;39:717-725. doi: 10.2337/dc16-0041
43. Neubauer S. The failing heart-an engine out of fuel. N Engl J Med. 2007;356:1140-1151. doi: 10.1056/NEJMra063052
44. Choi YS, de Mattos AB, Shao D, Li T, Nabben M, Kim M, Wang W, Tian R, Kolwicz SC Jr. Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion. J Mol Cell Cardiol. 2016;100:64-71. doi: 10.1016/j.yjmcc.2016.09.001
45. Drosatos K, Pollak NM, Pol CJ, Ntziachristos P, Willecke F, Valenti MC, Trent CM, Hu Y, Guo S, Aifantis I, Goldberg IJ. Cardiac myocyte KLF5 regulates Ppara expression and cardiac function. Circ Res. 2016;118:241-253. doi: 10.1161/CIRCRESAHA.115.306383
46. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207-258. doi: 10.1152/physrev.00015.2009
47. Khan RS, Lin Y, Hu Y, Son NH, Bharadwaj KG, Palacios C, Chokshi A, Ji R, Yu S, Homma S, Schulze PC, Tian R, Goldberg IJ. Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function. Am J Physiol Endocrinol Metab. 2013;305:E1339-E1347. doi: 10.1152/ajpendo.00349.2013
48. Dewey FE, Gusarova V, O'Dushlaine C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med. 2016;374:1123-1133. doi: 10.1056/NEJMoa1510926
49. Stitziel NO, Stirrups KE, Masca NG, Erdmann J, Ferrario PG, Konig IR, Weeke PE, Webb TR, Auer PL, Schick UM, Lu Y, Zhang H, Dube MP, et al; Myocardial Infarction G, Investigators CAEC. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med. 2016;374:1134-1144. doi: 10.1056/NEJMx160012