1,535
Views
0
CrossRef citations to date
0
Altmetric
Clinical Focus: Diabetes - Review

Sodium-glucose cotransporter 2 inhibitors and cardiovascular outcomes

Pages 398-408 | Received 04 Feb 2016, Accepted 17 Mar 2016, Published online: 07 Apr 2016

References

  • American Diabetes Association. (8) Cardiovascular disease and risk management. Diabetes Care. 2015;38(Suppl):S49–S57.
  • Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006;332:73–78.
  • Nwaneri C, Cooper H, Bowen-Jones D. Mortality in type 2 diabetes mellitus: magnitude of the evidence from a systematic review and meta-analysis. Br J Diabetes Vasc Dis. 2013;13:192–207.
  • Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829–841.
  • Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment. Lancet Diabetes Endocrinol. 2014;2:634–647.
  • Ohkubo Y, Kishikawa H, Araki E, et al. 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.
  • UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–853.
  • Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559.
  • ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572.
  • Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–139.
  • Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373:1765–1772.
  • Skyler JS, Bergenstal R, Bonow RO, et al. 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.
  • Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36:2288–2296.
  • Mannucci E, Dicembrini I, Lauria A, et al. Is glucose control important for prevention of cardiovascular disease in diabetes? Diabetes Care. 2013;36(Suppl 2):S259–S263.
  • Bethel MA, Sourij H. Impact of FDA guidance for developing diabetes drugs on trial design: from policy to practice. Curr Cardiol Rep. 2012;14:59–69.
  • 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.
  • Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–2471.
  • Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298:1189–1195.
  • 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.
  • Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–1188.
  • Yki-Järvinen H. The PROactive study: some answers, many questions. Lancet. 2005;366:1241–1242.
  • Guidance for industry: diabetes mellitus - evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Food and Drug Administration (Center for Drug Evaluation and Research); 2008 [cited 2015 Jun 23]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf
  • Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. European Medicines Agency; 2012 [cited 2015 Jun 23]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf
  • Authors/Task Force Members, Rydén L, Grant PJ, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34:3035–3087.
  • Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27:136–142.
  • Bays H. Sodium glucose co-transporter type 2 (SGLT2) inhibitors: targeting the kidney to improve glycemic control in diabetes mellitus. Diabetes Ther. 2013;4:195–220.
  • 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.
  • Hediger MA, Rhoads DB. Molecular physiology of sodium-glucose cotransporters. Physiol Rev. 1994;74:993–1026.
  • Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733–794.
  • Kashiwagi Y, Nagoshi T, Yoshino T, et al. Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice. PLoS ONE. 2015;10:e0130605.
  • DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14:5–14.
  • Janssen Pharmaceuticals Inc. Prescribing information (12/2015): INVOKANA (canagliflozin) tablets, for oral use; 2015 [cited 2016 Feb 29]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204042s013lbl.pdf
  • AstraZeneca Pharmaceuticals LP. Prescribing information (12/2015): FARXIGA (dapagliflozin) tablets, for oral use; 2015 [cited 2016 Feb 29]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202293s008lbl.pdf
  • Boehringer Ingelheim Pharmaceuticals Inc. Prescribing information (12/2015): JARDIANCE (empagliflozin) tablets, for oral use; 2015 [cited 2016 Feb 29]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204629s007lbl.pdf
  • Lapuerta P, Zambrowicz B, Strumph P, et al. Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diab Vasc Dis Res. 2015;12:101–110.
  • Poole RM, Dungo RT. Ipragliflozin: first global approval. Drugs. 2014;74:611–617.
  • Poole RM, Prossler JE. Tofogliflozin: first global approval. Drugs. 2014;74:939–944.
  • Markham A, Elkinson S. Luseogliflozin: first global approval. Drugs. 2014;74:945–950.
  • Whalen K, Miller S, Onge ES. The role of sodium-glucose co-transporter 2 inhibitors in the treatment of type 2 diabetes. Clin Ther. 2015;37:1150–1166.
  • Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75:33–59.
  • Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Investig. 2014;124:499–508.
  • Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Investig. 2014;124:509–514.
  • Merovci A, Mari A, Solis C, et al. Dapagliflozin lowers plasma glucose concentration and improves beta-cell function. J Clin Endocrinol Metabolism. 2015;100:1927–1932.
  • Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16:984–993.
  • Yang XP, Lai D, Zhong XY, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis. Eur J Clin Pharmacol. 2014;70:1149–1158.
  • Zhang M, Zhang L, Wu B, et al. Dapagliflozin treatment for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2014;30:204–221.
  • Scheen AJ. SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf. 2015;14:1879–1904.
  • Geerlings S, Fonseca V, Castro-Diaz D, et al. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014;103:373–381.
  • US Food and Drug Administration. Drug safety communication (04 December 2015): FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections; [cited 2016 Jan 18]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM475487.pdf
  • Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–1693.
  • US Food and Drug Administration. Drug safety communication (05 May 2015): FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood; [cited 2015 Jul 13]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf
  • Erondu N, Desai M, Ways K, et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38:1680–1686.
  • Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–1642.
  • Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
  • Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90–100.
  • Hirshberg B, Katz A. Cardiovascular outcome studies with novel antidiabetes agents: scientific and operational considerations. Diabetes Care. 2013;36(Suppl 2):S253–S258.
  • Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363:1410–1418.
  • Duckworth WC, Abraira C, Moritz TE, et al. The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial. J Diabetes Complications. 2011;25:355–361.
  • Goto A, Arah OA, Goto M, et al. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ. 2013;347:f4533.
  • Matthaei S, Bowering K, Rohwedder K, et al. Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care. 2015;38:365–372.
  • Wilding JP, Norwood P, T’Joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32:1656–1662.
  • Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013;67:1267–1282.
  • Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38:403–411.
  • Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013;36:3396–3404.
  • Inzucchi SE, Bergenstal RM, Buse JB, 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;38:140–149.
  • 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.
  • Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15:372–382.
  • Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217–2224.
  • Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1:208–219.
  • Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36:2508–2515.
  • Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34:2015–2022.
  • Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941–950.
  • Wysham CH. New perspectives in type 2 diabetes, cardiovascular risk, and treatment goals. Postgrad Med. 2010;122:52–60.
  • Fox CS, Pencina MJ, Wilson PW, et al. Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the framingham heart study. Diabetes Care. 2008;31:1582–1584.
  • Wilding JP. The importance of weight management in type 2 diabetes mellitus. Int J Clin Pract. 2014;68:682–691.
  • Look AHEAD trial. Look AHEAD; 2015 [cited 2015 Oct 21]. Available from: https://www.lookaheadtrial.org/public/home.cfm
  • Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–154.
  • Ferrannini G, Hach T, Crowe S, et al. Energy balance after sodium glucose cotransporter 2 (SGLT2) inhibition. Diabetes Care. 2015;38:1730–1735.
  • Bolinder J, Ljunggren Ö, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16:159–169.
  • Ridderstråle M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2:691–700.
  • Leiter LA, Yoon KH, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care. 2015;38:355–364.
  • Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet. 2014;383:1899–1911.
  • Zhang X, Zhao Q. Effects of dipeptidyl peptidase-4 inhibitors on blood pressure in patients with type 2 diabetes: a systematic review and meta-analysis. J Hypertens. 2016;34:167–175.
  • Wang B, Zhong J, Lin H, et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab. 2013;15:737–749.
  • Sun F, Wu S, Guo S, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110:26–37.
  • Sarafidis PA, Lasaridis AN, Nilsson PM, et al. Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase. J Hypertens. 2004;22:1769–1777.
  • Baker WL, Smyth LR, Riche DM, et al. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262–275.e9.
  • Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113:1213–1225.
  • Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38:420–428.
  • Weber MA, Mansfield TA, Cain VA, et al. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4:211–220.
  • Townsend RR, Machin I, Ren J, et al. reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension. J Clin Hypertens (Greenwich). 2016;18:43–52.
  • O’Brien E, Parati G, Stergiou G, et al. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31:1731–1768.
  • Majewski C, Bakris GL. Blood pressure reduction: an added benefit of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes. Diabetes Care. 2015;38:429–430.
  • Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15:853–862.
  • Thomson SC, Vallon V, Blantz RC. Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am J Physiol Renal Physiol. 2004;286:F8–15.
  • Abdul-Ghani MA, DeFronzo RA. Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport. J Intern Med. 2014;276:352–363.
  • Škrtić M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24:96–103.
  • 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.
  • Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180–1193.
  • Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8:330–339.
  • Howard BV, Robbins DC, Sievers ML, et al. LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study. Arterioscler Thromb Vasc Biol. 2000;20:830–835.
  • Jacobs DR Jr., Mebane IL, Bangdiwala SI, et al. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study. Am J Epidemiol. 1990;131:32–47.
  • Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5:150–159.
  • Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602–613.
  • Buse JB, Tan MH, Prince MJ, et al. The effects of oral anti-hyperglycaemic medications on serum lipid profiles in patients with type 2 diabetes. Diabetes Obes Metab. 2004;6:133–156.
  • Tziomalos K, Athyros VG, Karagiannis A, et al. Dyslipidemia induced by drugs used for the prevention and treatment of vascular diseases. Open Cardiovasc Med J. 2011;5:85–89.
  • Monami M, Lamanna C, Desideri CM, et al. DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv Ther. 2012;29:14–25.
  • Ptaszynska A, Hardy E, Johnsson E, et al. Effects of dapagliflozin on cardiovascular risk factors. Postgrad Med. 2013;125:181–189.
  • Mikhail N. Safety of canagliflozin in patients with type 2 diabetes. Curr Drug Saf. 2014;9:127–132.
  • Hach T, Gerich J, Salsali A, et al. Empagliflozin improves glycemic parameters and cardiovascular risk factors in patients with type 2 diabetes (T2DM): pooled data from four pivotal phase III trials. Diabetes. 2013;62(Suppl 1):LB19. (Abstract 69-LB)
  • Haas B, Eckstein N, Pfeifer V, et al. Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin. Nutr Diabetes. 2014;4:e143.
  • Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–242.
  • Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–1326.
  • White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–1335.
  • Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016 Feb 17. doi:10.1056/NEJMoa1506930. [Epub ahead of print].
  • Dormandy JA, Charbonnel B, Eckland DJ, 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;366:1279–1289.
  • Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360:2503–2515.
  • Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262–274.
  • Sonesson C, Johansson PA, Johnsson E, et al. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol. 2016;15:37.
  • FDA briefing document (NDA 202293): dapagliflozin tablets, 5 and 10 mg. US Food and Drug Administration; 2013 [cited 2015 Jul 20]. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf
  • List J, Sonesson C, Gause-Nilsson I, et al. No increased risk of early or late adjudicated cardiovascular events with dapagliflozin. Circulation. 2014;130(Suppl 2):A16682.
  • Leiter LA, Cefalu WT, De Bruin TW, et al. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62:1252–1262.
  • Cefalu WT, Leiter LA, De Bruin TW, et al. Dapagliflozin’s effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care. 2015;38:1218–1227.
  • FDA briefing document (NDA 204042): Invokana (canagliflozin) tablets. US Food and Drug Administration; 2013 [cited 2015 Jul 20]. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334550.pdf
  • Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the canagliflozin cardiovascular assessment study (CANVAS)–a randomized placebo-controlled trial. Am Heart J. 2013;166:217–223.e11.
  • Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). DECLARE-TIMI 58; [cited 2015 Jul 14]. Available from: https://clinicaltrials.gov/ct2/show/NCT01730534
  • CANVAS - CANagliflozin cardioVascular Assessment Study. CANVAS; [cited 2015 Jul 14]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01032629
  • A study of the effects of canagliflozin (JNJ-28431754) on renal endpoints in adult participants with type 2 diabetes mellitus (CANVAS-R) CANVAS-R. [cited 2015 Jul 14]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT01989754
  • Evaluation of the effects of canagliflozin on renal and cardiovascular outcomes in participants with diabetic nephropathy (CREDENCE). CREDENCE; [cited 2015 Jul 14]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT02065791
  • Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol. 2014;13:102.
  • Cardiovascular outcomes following treatment with ertugliflozin in participants with type 2 diabetes mellitus and established vascular disease (MK-8835-004). Ertugliflozin Cardiovascular Outcomes Trial; [cited 2015 July 20]. Available from: https://www.clinicaltrials.gov/ct2/show/record/NCT01986881
  • DeFronzo RA. The EMPA-REG study: what has it told us? A diabetologist’s perspective. J Diabetes Complications. 2016;30:1–2.
  • Kennedy M, Forgione N. The EMPA-REG OUTCOME study: what does it mean for primary care? Diabetes Prim Care Aust. 2015;1:29–32.
  • Scheen AJ. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 2016 Feb 5. doi:10.1016/j.diabet.2015.12.005. [Epub ahead of print].
  • Scheen AJ, Esser N, Paquot N. Antidiabetic agents: potential anti-inflammatory activity beyond glucose control. Diabetes Metab. 2015;41:183–194.
  • Jones BJ, Tan T, Bloom SR. Minireview: glucagon in stress and energy homeostasis. Endocrinology. 2012;153:1049–1054.
  • Ceriello A, Genovese S, Mannucci E, et al. Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol. 2015;3:929–930.
  • DECLARE-TIMI 58. TIMI Study Group; [cited 2015 Jul 22]. Available from: http://www.timi.org/index.php?page=declare-timi-58

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.