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02-02-2017 | Cardiovascular outcomes | Review | Article

Cardiovascular safety of non-insulin pharmacotherapy for type 2 diabetes

Journal: Cardiovascular Diabetology

Authors: James Xu, Rohan Rajaratnam

Publisher: BioMed Central

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Abstract

Patients with type 2 diabetes mellitus have a twofold increased risk of cardiovascular mortality compared with non-diabetic individuals. There is a growing awareness that glycemic efficacy of anti-diabetic drugs does not necessarily translate to cardiovascular safety. Over the past few years, there has been a number of trials evaluating the cardiovascular effects of anti-diabetic drugs. In this review, we seek to examine the cardiovascular safety of these agents in major published trials. Metformin has with-stood the test of time and remains the initial drug of choice. The sulfonylureas, despite being the oldest oral anti-diabetic drug, has been linked to adverse cardiovascular events and are gradually being out-classed by the various other second-line agents. The glitazones are contraindicated in heart failure. The incretin-based drugs have been at the fore-front of this era of cardiovascular safety trials and their performances have been reassuring, whereas the meglitinides and the alpha-glucosidase inhibitors still lack cardiovascular outcomes data. The sodium glucose cotransporter-2 inhibitors are an exciting new addition that has demonstrated a potential for cardiovascular benefit. Many of the currently available oral anti-diabetic agents have clinically relevant cardiovascular effects. The optimal approach to the reduction of cardiovascular risk in diabetic patients should focus on aggressive management of the standard cardiovascular risk factors rather than purely on intensive glycemic control.
Literature
1.
Preis SR, et al. Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005. Circulation. 2009;119(13):1728–35. CrossRefPubMedPubMedCentral
2.
Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–59. CrossRefPubMed
3.
Patel A, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72. CrossRefPubMed
4.
Duckworth W, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–39. CrossRefPubMed
5.
Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89. CrossRefPubMed
6.
Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs–insights from the rosiglitazone experience. N Engl J Med. 2013;369(14):1285–7. CrossRefPubMed
7.
WHO. Model lists of essential medicines. 2015 April 2015. http://​www.​who.​int/​medicines/​publications/​essentialmedicin​es/​en/​. Accessed 14 May 2016.
8.
Pernicova I, Korbonits M. Metformin–mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10(3):143–56. CrossRefPubMed
9.
DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541–9. CrossRefPubMed
10.
Knowler WC, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702):1677–86. CrossRefPubMed
11.
Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9. CrossRefPubMed
12.
Bakhashab S, et al. Metformin improves the angiogenic potential of human CD34(+) cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction. Cardiovasc Diabetol. 2016;15:27. CrossRefPubMedPubMedCentral
13.
Ahmed FW, et al. Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study. Cardiovasc Diabetol. 2016;15(1):116. CrossRefPubMedPubMedCentral
14.
Yu JW, et al. Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice. Cardiovasc Diabetol. 2016;15:88. CrossRefPubMedPubMedCentral
15.
United Kingdom Prospective Diabetes Study. 34: effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. The Lancet. 1998;352(9131):854–65. CrossRef
16.
Lamanna C, et al. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13(3):221–8. CrossRefPubMed
17.
Saenz A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;3:CD002966.
18.
Eurich DT, et al. Changes in labelling for metformin use in patients with type 2 diabetes and heart failure: documented safety outweighs theoretical risks. Open Med. 2011;5(1):e33–4. PubMedPubMedCentral
19.
Eurich DT, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail. 2013;6(3):395–402. CrossRefPubMed
20.
Kao J, et al. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004;93(11):1347–50. CrossRefPubMed
21.
Goergen SK, et al. Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology. 2010;254(1):261–9. CrossRefPubMed
22.
Baerlocher MO, Asch M, Myers A. Five things to know about…metformin and intravenous contrast. Can Med Assoc J. 2013;185(1):E78. CrossRef
23.
Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–9. CrossRefPubMed
24.
Garber AJ, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2016 Executive Summary. Endocr Pract. 2016;22(1):84–113. CrossRefPubMed
25.
Sola D, et al. Sulfonylureas and their use in clinical practice. Arch Med Sci. 2015;11(4):840–8. CrossRefPubMedPubMedCentral
26.
Proks P, et al. Sulfonylurea Stimulation of Insulin Secretion. Diabetes. 2002;51(Supplement 3):S368–76. CrossRefPubMed
27.
Hemmingsen B, et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;4:9008.
28.
United Kingdom Prospective Diabetes Study. 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med. 1998;128(3):165. CrossRef
29.
Massi-Benedetti M. Glimerpiride in type 2 diabetes mellitus: a review of the worldwide therapeutic experience. Clin Ther. 2003;25(3):799–816. CrossRefPubMed
30.
Lawrence CL, et al. Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K(ATP) channels. Br J Pharmacol. 2002;136(5):746–52. CrossRefPubMedPubMedCentral
31.
American Diabetes Association. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes: VI Supplementary report on nonfatal events in patients treated with tolbutamide. Diabetes. 1976;25(12):1129–53. CrossRef
32.
Garratt KN, et al. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1999;33(1):119–24. CrossRefPubMed
33.
Simpson SH, et al. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. Can Med Assoc J. 2006;174(2):169–74. CrossRef
34.
Roumie CL, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2012;157(9):601–10. CrossRefPubMedPubMedCentral
35.
Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15(10):938–53. CrossRefPubMed
36.
Giblett JP, et al. Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies. Cardiovasc Diabetol. 2016;15:99. CrossRefPubMedPubMedCentral
37.
Simpson SH, et al. Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol. 2015;3(1):43–51. CrossRefPubMed
38.
Fuhlendorff J, et al. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes. 1998;47(3):345–51. CrossRefPubMed
39.
Azimova K, San Z. Juan, and D. Mukherjee, Cardiovascular safety profile of currently available diabetic drugs. Ochsner J. 2014;14(4):616–32. PubMedPubMedCentral
40.
Black C, et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;2:4654.
41.
Holman RR, et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16):1463–76. CrossRefPubMed
42.
Schramm TK, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J. 2011;32(15):1900–8. CrossRefPubMed
43.
Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36(34):2288–96. CrossRefPubMed
44.
Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106–18. CrossRefPubMed
45.
Goldberg RB, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28(7):1547–54. CrossRefPubMed
46.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71. CrossRefPubMed
47.
Home PD, et al. Rosiglitazone evaluated for cardiovascular outcomes–an interim analysis. N Engl J Med. 2007;357(1):28–38. CrossRefPubMed
48.
Home PD, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373(9681):2125–35. CrossRefPubMed
49.
Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89. CrossRefPubMed
50.
Lincoff AM, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180–8. CrossRefPubMed
51.
Hernandez AV, et al. Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials. Am J Cardiovasc Drugs. 2011;11(2):115–28. CrossRefPubMed
52.
Gerstein HC, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368(9541):1096–105. CrossRefPubMed
53.
Ponikowski P, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016.
54.
Krische D. The glitazones: proceed with caution. West J Med. 2000;173(1):54–7. CrossRefPubMed
55.
Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60(4):470–512. CrossRefPubMedPubMedCentral
56.
Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298(2):194–206. CrossRefPubMed
57.
Craddy P, Palin HJ, Johnson KI. Comparative effectiveness of dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed treatment comparison. Diabetes Ther. 2014;5(1):1–41. CrossRefPubMedPubMedCentral
58.
Davidson JA. Advances in therapy for type 2 diabetes: GLP-1 receptor agonists and DPP-4 inhibitors. Cleve Clin J Med. 2009;76(Suppl 5):S28–38. CrossRefPubMed
59.
Fadini GP, Avogaro A. Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vasc Pharmacol. 2011;55(1–3):10–6. CrossRef
60.
Scirica BM, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. CrossRefPubMed
61.
Scirica BM, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130(18):1579–88. CrossRefPubMed
62.
White WB, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35. CrossRefPubMed
63.
Zannad F, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067–76. CrossRefPubMed
64.
Green JB, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232–42. CrossRefPubMed
65.
Nakamura T, et al. Cardiovascular efficacy of sitagliptin in patients with diabetes at high risk of cardiovascular disease: a 12- month follow- up. Cardiovasc Diabetol. 2016;15:54. CrossRefPubMedPubMedCentral
66.
Maruhashi T, et al. Long- term effect of sitagliptin on endothelial function in type 2 diabetes: a sub- analysis of the PROLOGUE study. Cardiovasc Diabetol. 2016;15(1):134. CrossRefPubMedPubMedCentral
67.
Rosenstock J, et al. Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol. 2015;14:57. CrossRefPubMedPubMedCentral
68.
Li L, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610. CrossRefPubMedPubMedCentral
69.
Filion KB, et al. A multicenter observational study of incretin-based drugs and heart failure. N Engl J Med. 2016;374(12):1145–54. CrossRefPubMed
70.
Toh S, et al. Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin, and other antihyperglycemic drugs: a retrospective cohort study. Ann Intern Med. 2016;164(11):705–14. CrossRefPubMed
71.
Ou HT, et al. Risks of cardiovascular diseases associated with dipeptidyl peptidase-4 inhibitors and other antidiabetic drugs in patients with type 2 diabetes: a nation-wide longitudinal study. Cardiovasc Diabetol. 2016;15:41. CrossRefPubMedPubMedCentral
72.
FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. 2016. http://​www.​fda.​gov/​Drugs/​DrugSafety/​ucm486096.​htm. Accessed 23 May 2016.
73.
Shyangdan DS, et al. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;10:CD006423.
74.
Sun F, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther. 2015;37(1):225–41. CrossRefPubMed
75.
Katout M, et al. Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression. Am J Hypertens. 2014;27(1):130–9. CrossRefPubMed
76.
Lebovitz HE, Banerji MA. Non-insulin injectable treatments (glucagon-like peptide-1 and its analogs) and cardiovascular disease. Diabetes Technol Ther. 2012;14(Suppl 1):S43–50. PubMed
77.
Angeli FS, Shannon RP. Incretin-based therapies: can we achieve glycemic control and cardioprotection? J Endocrinol. 2014;221(1):T17–30. CrossRefPubMed
78.
Pfeffer MA, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57. CrossRefPubMed
79.
Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. CrossRefPubMedPubMedCentral
80.
Kumarathurai P, et al. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on systolic function in patients with coronary artery disease and type 2 diabetes: a randomized double-blind placebo-controlled crossover study. Cardiovasc Diabetol. 2016;15(1):105. CrossRefPubMedPubMedCentral
81.
Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. CrossRefPubMed
82.
Ferdinand KC, et al. Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol. 2016;15:38. CrossRefPubMedPubMedCentral
83.
Clar C, et al. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012;2(5):e001007. CrossRefPubMedPubMedCentral
84.
Hanefeld M, Forst T. Dapagliflozin, an SGLT2 inhibitor, for diabetes. Lancet. 2010;375(9733):2196–8. CrossRefPubMed
85.
Musso G, et al. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med. 2012;44(4):375–93. CrossRefPubMed
86.
Vasilakou D, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74. CrossRefPubMed
87.
Hasan FM, Alsahli M, Gerich JE. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res Clin Pract. 2014;104(3):297–322. CrossRefPubMed
88.
Baker WL, et al. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8(4):262–75. CrossRefPubMed
89.
Oelze M, et al. 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(11):e112394. CrossRefPubMedPubMedCentral
90.
Fitchett D, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37(19):1526–34. CrossRefPubMedPubMedCentral
91.
Wu JH, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411–9. CrossRefPubMed
92.
Roden M, et al. Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naive patients with type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial. Cardiovasc Diabetol. 2015;14:154. CrossRefPubMedPubMedCentral
93.
Sonesson C, et al. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol. 2016;15:37. CrossRefPubMedPubMedCentral
94.
Anderson JE, Wright EE, Shaefer CF. Empagliflozin: role in treatment options for patients with type 2 diabetes mellitus. Diabetes Ther. 2016. doi: 10.​1007/​s13300-016-0211-x PubMedPubMedCentral
95.
DiNicolantonio JJ, Bhutani J, O’Keefe JH. Acarbose: safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes. Open Heart. 2015;2(1):e000327. CrossRefPubMedPubMedCentral
96.
Van de Laar FA, et al. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;2:CD003639.
97.
Arakawa M, et al. Miglitol suppresses the postprandial increase in interleukin 6 and enhances active glucagon-like peptide 1 secretion in viscerally obese subjects. Metabolism. 2008;57(9):1299–306. CrossRefPubMed
98.
Hariya N, et al. Switching alpha-glucosidase inhibitors to miglitol reduced glucose fluctuations and circulating cardiovascular disease risk factors in type 2 diabetic Japanese patients. Drugs R D. 2014;14(3):177–84. CrossRefPubMedPubMedCentral
99.
Shimabukuro M, et al. Miglitol, alpha-glycosidase inhibitor, reduces visceral fat accumulation and cardiovascular risk factors in subjects with the metabolic syndrome: a randomized comparable study. Int J Cardiol. 2013;167(5):2108–13. CrossRefPubMed
100.
Chiasson J-L, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359(9323):2072–7. CrossRefPubMed
101.
Chiasson JL, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290(4):486–94. CrossRefPubMed

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