Cardioprotective anti-hyperglycaemic medications: a review of clinical trials

European Heart Journal

Volumn 39, Issue 25, 2018, Pages 2368c-2375c

  Ahmed, Haitham M ^a   Khraishah, Haitham ^b   Cho, Leslie ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

^b BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

Author keywords

Cardiac death Sodium glucose; Diabetes mellitus Diabetes complications; Glucagon like peptide 1 receptor; Hypoglycaemic agents; transport proteins

Indexed keywords

ANTIDIABETIC AGENT; CANAGLIFLOZIN; EMPAGLIFLOZIN; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; LIRAGLUTIDE; SEMAGLUTIDE; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; CARDIOTONIC AGENT;

CARDIOVASCULAR MORTALITY; CHRONIC KIDNEY FAILURE; DIABETIC PATIENT; DRUG INDICATION; DRUG MECHANISM; DRUG SAFETY; FOOD AND DRUG ADMINISTRATION; HEART PROTECTION; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; REVIEW; CARDIOVASCULAR DISEASE; CLINICAL TRIAL (TOPIC); COMPLICATION; DIABETIC CARDIOMYOPATHY;

CARDIOTONIC AGENTS; CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; DIABETES MELLITUS, TYPE 2; DIABETIC CARDIOMYOPATHIES; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; HUMANS; HYPOGLYCEMIC AGENTS; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS;

EID: 85050627197     PISSN: 0195668X     EISSN: 15229645     Source Type: Journal    
DOI: 10.1093/eurheartj/ehx668     Document Type: Review

References (106)

1. International Diabetes Federation. IDF diabetes atlas. 2014.
2. Emerging Risk Factors Collaboration; Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF, Holme I, Njolstad I, Fletcher A, Nilsson P, Lewington S, Collins R, Gudnason V, Thompson SG, Sattar N, Selvin E, Hu FB, Danesh J. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829–841.
3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The diabetes control and complications trial research group. N Engl J Med 1993;329:977–986.
4. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103–117.
5. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de GBE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–2572.
6. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EA, Howard BV, Kirkman MS, Kosiborod M, Reaven P, Sherwin RS; American Diabetes Association, American College of Cardiology Foundation, American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: implications of the accord, advance, and va diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College Of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol 2009;53:298–304.
7. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewald WT. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364: 818–828.
8. Gerstein HC, Riddle MC, Kendall DM, Cohen RM, Goland R, Feinglos MN, Kirk JK, Hamilton BP, Ismail-Beigi F, Feeney P, Group AS. Glycemia treatment strategies in the action to control cardiovascular risk in diabetes (ACCORD) trial. Am J Cardiol 2007;99:34i–43i.
9. Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, Zhou Z, Tang W, Zhao J, Cui L, Zou D, Wang D, Li H, Liu C, Wu G, Shen J, Zhu D, Wang W, Shen W, Ning G; SPREAD-DIMCAD Investigators. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013;36:1304–1311.
10. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2016;164:740–751.
11. 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 OUTCOMES Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128.
12. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657.
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; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375:311–322.
14. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsboll T; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–1844.
15. UFaD Administration. Guidance for industry. Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008
16. Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs–insights from the rosiglitazone experience. N Engl J Med 2013;369:1285–1287.
17. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581–2586.
18. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J 2015;36:2288–2296.
19. Syed SH, Gosavi S, Shami W, Bustamante M, Farah Z, Teleb M, Abbas A, Said S, Mukherjee D. A review of sodium glucose co-transporter 2 inhibitors canagliflozin, dapagliflozin and empagliflozin. Cardiovasc Hematol Agents Med Chem 2015;13:105–112.
20. Harada N, Inagaki N. Role of sodium-glucose transporters in glucose uptake of the intestine and kidney. J Diabetes Investig 2012;3:352–353.
21. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev 2011;91:733–794.
22. Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thévenet J, Beaucamps C, Delalleau N, Popescu I, Malaisse WJ, Sener A, Deprez B, Abderrahmani A, Staels B, Pattou F. Inhibition of the glucose transporter sglt2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med 2015;21:512–517.
23. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Solomon SD, Tardif JC; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373: 2247–2257.
24. Paneni F, Lüscher TF. Cardiovascular protection in the treatment of type 2 diabetes: a review of clinical trial results across drug classes. Am J Cardiol 2017; 120:S17–S27.
25. ClinicalTrials.gov. Exenatide study of cardiovascular event lowering trial (exscel): a trial to evaluate cardiovascular outcomes after treatment with exenatide once weekly in patients with type 2 diabetes mellitus. 2017. https://clinicaltrials.gov/ct2/show/NCT01144338 (6 November 2017).
26. ClinicalTrials.gov. Rewind: researching cardiovascular events with a weekly incretin in diabetes. 2017. https://clinicaltrials.gov/ct2/show/NCT01394952 (6 November 2017).
27. ClinicalTrials.gov. Harmony: effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes mellitus. 2017. https://clinicaltrials.gov/ct2/show/NCT02465515 (6 November 2017).
28. ClinicalTrials.gov. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (declare-timi58). 2016. https://clinicaltrials.gov/ct2/show/NCT01730534 (6 November 2017).
29. Halimi S, Verges B. Adverse effects and safety of sglt-2 inhibitors. Diabetes Metab 2014;40:S28–S34.
30. Saad M, Mahmoud AN, Elgendy IY, Abuzaid A, Barakat AF, Elgendy AY, Al-Ani M, Mentias A, Nairooz R, Bavry AA, Mukherjee D. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type ii diabetes mellitus: a meta-analysis of placebo-controlled randomized trials. Int J Cardiol 2017;228:352–358.
31. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013;159:262–274.
32. UFaD Administration. FDA approves jardiance to reduce cardiovascular death in adults with type 2 diabetes. 2016
33. VR investigators. Empagliflozin and clinical outcomes in patients with type 2 diabetes, established cardiovascular disease and chronic kidney disease. Circulation 2017; doi: 10.1161/CIRCULATIONAHA.117.028268.
34. VR trial. Eur Heart J 2016;37:1526–1534.
35. VR trial. Eur Heart J 2017; doi: 10.1093/eurheartj/ehx511.
36. ClinicalTrials.gov. Empagliflozin outcome trial in patients with chronic heart failure with reduced ejection fraction (emperor-reduced). 2017. https://clinicaltrials.gov/ct2/show/NCT03057977 (6 November 2017).
37. ClinicalTrials.gov. Empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction (emperor-preserved). 2017. https://clinicaltrials.gov/ct2/show/NCT03057951 (6 November 2017).
38. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen ME, Thuresson M, Arya N, Bodegård J, Hammar N, Fenici P; CVD-REAL Investigators and Study Group. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the cvd-real study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation 2017;136:249–259.
39. Birkeland KI, Jørgensen ME, Carstensen B, Persson F, Gulseth HL, Thuresson M, Fenici P, Nathanson D, Nyström T, Eriksson JW, Bodegård J, Norhammar A. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (cvd-real nordic): a multinational observational analysis. Lancet Diabetes Endocrinol 2017;5:709–717.
40. Baggio LL, Drucker DJ. Biology of incretins: Glp-1 and gip. Gastroenterology 2007;132:2131–2157.
41. Deacon CF, Ahren B. Physiology of incretins in health and disease. Rev Diabet Stud 2011;8:293–306.
42. Gautier JF, Choukem SP, Girard J. Physiology of incretins (gip and glp-1) and abnormalities in type 2 diabetes. Diabetes Metab 2008;34(Suppl 2):S65–S72.
43. Pinelli NR, Hurren KM. Efficacy and safety of long-acting glucagon-like peptide-1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: a systematic review and meta-analysis. Ann Pharmacother 2011;45:850–860.
44. Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab 2017;19:524–536.
45. Drucker DJ, Sherman SI, Bergenstal RM, Buse JB. The safety of incretin-based therapies–review of the scientific evidence. J Clin Endocrinol Metab 2011;96: 2027–2031.
46. Lunati ME, Grancini V, Colombo C, Palmieri E, Resi V, Perrino M, Orsi E, Fugazzola L. Basal and stimulated calcitonin levels in patients with type 2 diabetes did not change during 1 year of liraglutide treatment. Metabolism 2016; 65:1–6.
47. Koehler JA, Baggio LL, Lamont BJ, Ali S, Drucker DJ. Glucagon-like peptide-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice. Diabetes 2009;58:2148–2161.
48. Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care 2009;32:834–838.
49. Samson SL, Garber AJ. A plethora of glp-1 agonists: decisions about what to use and when. Curr Diab Rep 2016;16:120.
50. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens 2014;8:262–275.e9.
51. Weir MR, Januszewicz A, Gilbert RE, Vijapurkar U, Kline I, Fung A, Meininger G. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens (Greenwich) 2014;16:875–882.
52. Scheen AJ. Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on sglt2 inhibitors and empa-reg outcome. Diabetes Res Clin Pract 2016;121:204–214.
53. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 2013;15:853–862.
54. Lonn EM, Bosch J, Lopez-Jaramillo P, Zhu J, Liu L, Pais P, Diaz R, Xavier D, Sliwa K, Dans A, Avezum A, Piegas LS, Keltai K, Keltai M, Chazova I, Peters RJ, Held C, Yusoff K, Lewis BS, Jansky P, Parkhomenko A, Khunti K, Toff WD, Reid CM, Varigos J, Leiter LA, Molina DI, McKelvie R, Pogue J, Wilkinson J, Jung H, Dagenais G, Yusuf S, Investigators H. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009–2020.
55. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of sglt2 inhibition. Diabetologia 2017;60:215–225.
56. Verma S, McMurray JJV, Cherney DZI. The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition: the search for the sweet spot in heart failure. JAMA Cardiol 2017;2:939.
57. Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2014;16:457–466.
58. Heise T, Seman L, Macha S, Jones P, Marquart A, Pinnetti S, Woerle HJ, Dugi K. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther 2013;4:331–345.
59. Gore MO, McGuire DK. A test in context: hemoglobin A1c and cardiovascular disease. J Am Coll Cardiol 2016;68:2479–2486.
60. Madaan T, Akhtar M, Najmi AK. Sodium glucose cotransporter 2 (SGLT2) inhibitors: current status and future perspective. Eur J Pharm Sci 2016;93: 244–252.
61. Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D, DeFronzo RA, Norton L, Abdul-Ghani M. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care 2016;39:2036–2041.
62. Kanbay M, Jensen T, Solak Y, Le M, Roncal-Jimenez C, Rivard C, Lanaspa MA, Nakagawa T, Johnson RJ. Uric acid in metabolic syndrome: from an innocent bystander to a central player. Eur J Intern Med 2016;29:3–8.
63. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223–2233.
64. Rosenstock J, Aggarwal N, Polidori D, Zhao Y, Arbit D, Usiskin K, Capuano G, Canovatchel W, Canagliflozin DIASG. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012;35:1232–1238.
65. 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.
66. Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia 2009;52:691–697.
67. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587–597.
68. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC; EMAP-REG RENAL Trial Investigators. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014;2:369–384.
69. Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol 2017;28:368–375.
70. Verma S, Garg A, Yan AT, Gupta AK, Al-Omran M, Sabongui A, Teoh H, Mazer CD, Connelly KA. Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the empa-reg outcome trial? Diabetes Care 2016;39:e212–e213.
71. Pessoa TD, Campos LC, Carraro-Lacroix L, Girardi AC, Malnic G. Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on naþ/hþ exchanger isoform 3 activity in the renal proximal tubule. J Am Soc Nephrol 2014;25:2028–2039.
72. Inoue BH, dos Santos L, Pessoa TD, Antonio EL, Pacheco BP, Savignano FA, Carraro-Lacroix LR, Tucci PJ, Malnic G, Girardi AC. Increased nhe3 abundance and transport activity in renal proximal tubule of rats with heart failure. Am J Physiol Regul Integr Comp Physiol 2012;302:R166–R174.
73. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol 2017;2:1025.
74. Nakamura TY, Iwata Y, Arai Y, Komamura K, Wakabayashi S. Activation of naþ/hþ exchanger 1 is sufficient to generate ca2þ signals that induce cardiac hypertrophy and heart failure. Circ Res 2008;103:891–899.
75. Baartscheer A, Schumacher CA, Wust RC, Fiolet JW, Stienen GJ, Coronel R, Zuurbier CJ. Empagliflozin decreases myocardial cytoplasmic naþ through inhibition of the cardiac naþ/hþ exchanger in rats and rabbits. Diabetologia 2017;60:568–573.
76. Ferrannini E, Mark M, Mayoux E. Cv protection in the empa-reg outcome trial: a “thrifty substrate” hypothesis. Diabetes Care 2016;39:1108–1114.
77. Kaptoge S, Seshasai S, Gao P, Freitag DF, Butterworth AS, Borglykke A, Di Angelantonio E, Gudnason V, Rumley A, Lowe GD, Jørgensen T, Danesh J. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014;35:578–589.
78. Karbach S, Wenzel P, Waisman A, Munzel T, Daiber A. Enos uncoupling in cardiovascular diseases–the role of oxidative stress and inflammation. Curr Pharm Des 2017;20:3579–3594.
79. Oelze M, Kröller-Schön S, Welschof P, Jansen T, Hausding M, Mikhed Y, Stamm P, Mader M, Zinßius E, Agdauletova S, Gottschlich A, Steven S, Schulz E, Bottari SP, Mayoux E, Münzel T, Daiber A, Cignarella A. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One 2014;9:e112394.
80. Steven S, Oelze M, Hanf A, Kröller-Schön S, Kashani F, Roohani S, Welschof P, Kopp M, Gödtel-Armbrust U, Xia N, Li H, Schulz E, Lackner KJ, Wojnowski L, Bottari SP, Wenzel P, Mayoux E, Münzel T, Daiber A. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol 2017;13:370–385.
81. Scheen AJ, Esser N, Paquot N. Antidiabetic agents: potential anti-inflammatory activity beyond glucose control. Diabetes Metab 2015;41:183–194.
82. Kusaka H, Koibuchi N, Hasegawa Y, Ogawa H, Kim-Mitsuyama S. Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in predia-betic rats with metabolic syndrome. Cardiovasc Diabetol 2016;15:157.
83. Brown AJM, Lang C, McCrimmon R, Struthers A. Does dapagliflozin regress left ventricular hypertrophy in patients with type 2 diabetes? A prospective, double-blind, randomised, placebo-controlled study. BMC Cardiovasc Disord 2017;17:229.
84. Larsen EL, Cejvanovic V, Kjær LK, Vilsbøll T, Knop FK, Rungby J, Poulsen HE. The effect of empagliflozin on oxidative nucleic acid modifications in patients with type 2 diabetes: protocol for a randomised, double-blinded, placebo-controlled trial. BMJ Open 2017;7:e014728.
85. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; 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.
86. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–1335.
87. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR; TECOS Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–242.
88. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev 2012;33:187–215.
89. Zhong J, Rao X, Rajagopalan S. An emerging role of dipeptidyl peptidase 4 (dpp4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis 2013;226:305–314.
90. Steven SHM, Kröller-Schön S, Mader M, Mikhed Y, Stamm P, Zinßius E, Pfeffer A, Welschof P, Agdauletova S, Sudowe S, Li H, Oelze M, Schulz E, Klein T, Münzel T, Daiber A. Gliptin and glp-1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide-induced endotoxemia. Basic Res Cardiol 2015;110:6.
91. Vellecco V, Mitidieri E, Gargiulo A, Brancaleone V, Matassa D, Klein T, Esposito F, Cirino G, Bucci M. Vascular effects of linagliptin in non-obese diabetic mice are glucose-independent and involve positive modulation of the endothelial nitric oxide synthase (eNOS)/caveolin-1 (CAV-1) pathway. Diabetes Obes Metab 2016;18:1236–1243.
92. Darsalia V, Larsson M, Lietzau G, Nathanson D, Nyström T, Klein T, Patrone C. Gliptin-mediated neuroprotection against stroke requires chronic pretreatment and is independent of glucagon-like peptide-1 receptor. Diabetes Obes Metab 2016;18:537–541.
93. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, Le Roux CW, Violante Ortiz R, Jensen CB, Wilding JP, Obesity S; Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015;373:11–22.
94. Plutzky J, Garber A, Falahati A, Toft AD, Poulter NR. Reductions in lipids and CV risk markers in patients with type 2 diabetes treated with liraglutide: a meta-analysis. Can J Diabetes 2009;33:209–210.
95. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, Hale PM, Zdravkovic M, Blonde L; LEAD-4 Study Investigators. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (lead-4 metþtzd). Diabetes Care 2009;32:1224–1230.
96. Ceriello A, Novials A, Canivell S, La Sala L, Pujadas G, Esposito K, Testa R, Bucciarelli L, Rondinelli M, Genovese S. Simultaneous glp-1 and insulin administration acutely enhances their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. Diabetes Care 2014;37:1938–1943.
97. Drucker DJ, Rosen CF. Glucagon-like peptide-1 (glp-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology. Diabetologia 2011;54: 2741–2744.
98. Wang XHM, Weng SY, Kim YO, Steven S, Klein T, Daiber A, Schuppan D. Gliptins suppress inflammatory macrophage activation to mitigate inflammation, fibrosis, oxidative stress, and vascular dysfunction in models of nonalcoholic steatohepatitis and liver fibrosis. Antioxid Redox Signal 2017; doi: 10.1089/ars.2016.6953.
99. Lebherz CSG, Möllmann J, Kahles F, Schwarz M, Brünsing J, Dimkovic N, Koch A, Trautwein C, Flöge J, Marx N, Tacke F, Lehrke M. Glp-1 levels predict mortality in patients with critical illness as well as end-stage renal disease. Am J Med 2017;130:833–841.
100. Kröller-Schön S, Knorr M, Hausding M, Oelze M, Schuff A, Schell R, Sudowe S, Scholz A, Daub S, Karbach S, Kossmann S, Gori T, Wenzel P, Schulz E, Grabbe S, Klein T, Münzel T, Daiber A. Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition. Cardiovasc Res 2012;96:140–149.
101. Lønborg J, Vejlstrup N, Kelbæk H, Bøtker HE, Kim WY, Mathiasen AB, Jørgensen E, Helqvist S, Saunamäki K, Clemmensen P, Holmvang L, Thuesen L, Krusell LR, Jensen JS, Køber L, Treiman M, Holst JJ, Engstrøm T. Exenatide reduces reperfusion injury in patients with st-segment elevation myocardial infarction. Eur Heart J 2012;33:1491–1499.
102. Woo JS, Kim W, Ha SJ, Kim JB, Kim SJ, Kim WS, Seon HJ, Kim KS. Cardioprotective effects of exenatide in patients with st-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study. Arterioscler Thromb Vasc Biol 2013;33:2252–2260.
103. Chen WR, Hu SY, Chen YD, Zhang Y, Qian G, Wang J, Yang JJ, Wang ZF, Tian F, Ning QX. Effects of liraglutide on left ventricular function in patients with st-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am Heart J 2015;170:845–854.
104. 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;316:500–508.
105. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab 2016;24:15–30.
106. Steven S, Jurk K, Kopp M, Kröller-Schön S, Mikhed Y, Schwierczek K, Roohani S, Kashani F, Oelze M, Klein T, Tokalov S, Danckwardt S, Strand S, Wenzel P, Münzel T, Daiber A. Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitro-oxidative stress and platelet activation in endotoxae-mic mice. Br J Pharmacol 2017;174:1620–1632.