A Multifactorial Approach to Reduce Cardiovascular Disease in Type 2 Diabetes Mellitus: Now More Than Ever

References

• Wannamethee SG, Shaper AG, Whincup PH, et al. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med. 2011;171:404–410.
   PubMedGoogle Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Forst T, Hanefeld M, Jacob S, et al. Association of sulphonylurea treatment with all-cause and cardiovascular mortality: a systematic review and meta-analysis of observational studies. Diab Vasc Dis Res. 2013;10:302–314.
   PubMed Web of Science ®Google Scholar
• Rados DV, Pinto LC, Remonti LR, et al. Sulfonylureas are not associated with increased mortality: meta-analysis and trial sequential analysis of randomized clinical trials. American Diabetes Association 2015 Scientific Sessions; 2015 Jun 6; Boston, MA. Abstract 16-OR [cited 2015 Dec 22]. Available from: http://app.core-apps.com/tristar-ada15/abstract/160858d53930b598d64b10f39308a7de
   Google Scholar
• Simpson SH, Lee J, Choi S, et al. Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol. 2015;3:43–51.
   PubMed Web of Science ®Google Scholar
• Rao AD, Kuhadiya N, Reynolds K, et al. Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: a meta-analysis of observational studies. Diabetes Care. 2008;31:1672–1678.
   PubMed Web of Science ®Google Scholar
• Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589.
   PubMed Web of Science ®Google Scholar
• Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013;1:140–151.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• White WB, Pratley R, Fleck P, et al. Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:668–673.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122:16–27.
   PubMed Web of Science ®Google Scholar
• Monami M, Dicembrini I, Nardini C, et al. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16:38–47.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Wu S, Sun F, Zhang Y, et al. The cardiovascular effects of glucagon-like peptide-1 receptor agonists: a trial sequential analysis of randomized controlled trials. J Clin Pharm Ther. 2014;39:7–13.
   PubMed Web of Science ®Google Scholar
• Zannad F, Cannon CP, Cushman WC, 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;385:2067–2076.
   PubMed Web of Science ®Google Scholar
• American Diabetes Association news release. First CVD outcome trial of a GLP-1 agonist finds no cardiac risk or benefit. 2015 Jun 8 [cited 2015 Dec 22]. Available from: http://www.diabetes.org/newsroom/press-releases/2015/elixa.html
   Google Scholar
• Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015. doi:10.1056/NEJMoa1504720.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• BI 10773 (empagliflozin) cardiovascular outcome event trial in type 2 diabetes mellitus patients (EMPA-REG OUTCOME) [cited 2015 Dec 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT01131676
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes mellitus [cited 2015 Dec 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT02465515
   Google Scholar
• 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 [cited 2015 Dec 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT01144338
   Google Scholar
• Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58) [cited 2015 Dec 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT01730534
   Google Scholar
• Researching cardiovascular events with a weekly incretin in diabetes (REWIND) [cited 2015 Dec 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT01394952
   Google Scholar
• Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results – a long term evaluation (LEADER®) [cited 2015 Dec 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT01179048?term=liraglutide+effec
   Google Scholar
• Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–853.
   PubMed Web of Science ®Google Scholar
• ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559.
   PubMed Web of Science ®Google Scholar
• Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288–2298.
   PubMed Web of Science ®Google Scholar
• Siraj ES, Rubin DJ, Riddle MC, et al. Insulin dose and cardiovascular mortality in the ACCORD trial. Diabetes Care. 2015;38:2000–2008.
   PubMed Web of Science ®Google Scholar
• American Diabetes Association. 6. Glycemic targets. Diabetes Care. 2015;38(Supplement 1):S33–S40.
   PubMed Web of Science ®Google Scholar
• American Diabetes Association. 8. Cardiovascular disease and risk management. Diabetes Care. 2015;38(Supplement 1):S49–S57.
   PubMed Web of Science ®Google Scholar
• James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint national committee (jnc 8). JAMA. 2014;311:507–520.
   PubMed Web of Science ®Google Scholar
• Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 suppl 2):S1–S45.
   PubMed Web of Science ®Google Scholar
• Vazquez-Benitez G, Desai JR, Xu S, et al. Preventable major cardiovascular events associated with uncontrolled glucose, blood pressure, and lipids and active smoking in adults with diabetes with and without cardiovascular disease: a contemporary analysis. Diabetes Care. 2015;38:905–912.
   PubMed Web of Science ®Google Scholar
• Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703–713.
   PubMed Web of Science ®Google Scholar
• Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–1585.
   PubMed Web of Science ®Google Scholar
• Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev. 2013;10:Cd008277.
   PubMed Web of Science ®Google Scholar
• Wright JT Jr., Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421–2431.
   PubMed Web of Science ®Google Scholar
• Leenen FH, Nwachuku CE, Black HR, et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension. 2006;48:374–384.
   PubMed Web of Science ®Google Scholar
• ALLHAT Officers. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2002;288:2981–2997.
   PubMed Web of Science ®Google Scholar
• Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5:150–159.
   PubMedGoogle Scholar
• Vakkilainen J, Steiner G, Ansquer JC, et al. Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS). Circulation. 2003;107:1733–1737.
   PubMed Web of Science ®Google Scholar
• Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.
   PubMed Web of Science ®Google Scholar
• Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep. 2012;14:1–10.
   PubMed Web of Science ®Google Scholar
• Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117–125.
   PubMed Web of Science ®Google Scholar
• Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15.
   PubMed Web of Science ®Google Scholar
• Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450–458.
   PubMed Web of Science ®Google Scholar
• Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724–730.
   PubMed Web of Science ®Google Scholar
• American Diabetes Association. Fast facts: data and statistics about diabetes [ Revised 2015 Mar; cited 2015 Dec 22]. Available from: http://professional.diabetes.org/ResourcesForProfessionals.aspx?cid=91777&loc=dorg-statistics
   Google Scholar
• Bogers RP, Bemelmans WJ, Hoogenveen RT, et al. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels: a meta-analysis of 21 cohort studies including more than 300 000 persons. Arch Intern Med. 2007;167:1720–1728.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Wing RR. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. 2010;170:1566–1575.
   PubMed Web of Science ®Google Scholar
• Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481–1486.
   PubMed Web of Science ®Google Scholar
• Rock CL, Flatt SW, Pakiz B, et al. Weight loss, glycemic control, and cardiovascular disease risk factors in response to differential diet composition in a weight loss program in type 2 diabetes: a randomized controlled trial. Diabetes Care. 2014;37:1573–1580.
   PubMed Web of Science ®Google Scholar
• Qin R, Chen T, Lou Q, et al. Excess risk of mortality and cardiovascular events associated with smoking among patients with diabetes: meta-analysis of observational prospective studies. Int J Cardiol. 2013;167:342–350.
   PubMed Web of Science ®Google Scholar
• Pan A, Wang Y, Talaei M, et al. Relation of smoking with total mortality and cardiovascular events among patients with diabetes: a meta-analysis and systematic review. Circulation. 2015;132:1795–1804.
   Web of Science ®Google Scholar
• Nilsson PM, Gudbjornsdottir S, Eliasson B, et al. Smoking is associated with increased HbA1c values and microalbuminuria in patients with diabetes–data from the National Diabetes Register in Sweden. Diabetes Metab. 2004;30:261–268.
   PubMed Web of Science ®Google Scholar
• Hirai FE, Moss SE, Klein BE, et al. Severe hypoglycemia and smoking in a long-term type 1 diabetic population: Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care. 2007;30:1437–1441.
   PubMed Web of Science ®Google Scholar
• Voulgari C, Katsilambros N, Tentolouris N. Smoking cessation predicts amelioration of microalbuminuria in newly diagnosed type 2 diabetes mellitus: a 1-year prospective study. Metabolism. 2011;60:1456–1464.
   PubMed Web of Science ®Google Scholar
• Daniel Roth H, Roth AB, Liu X. Health risks of smoking compared to Swedish snus. Inhal Toxicol. 2005;17:741–748.
   PubMed Web of Science ®Google Scholar
• Piano MR, Benowitz NL, Fitzgerald GA, et al. Impact of smokeless tobacco products on cardiovascular disease: implications for policy, prevention, and treatment: a policy statement from the American Heart Association. Circulation. 2010;122:1520–1544.
   PubMed Web of Science ®Google Scholar
• Gaede P, Vedel P, Parving HH, et al. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet. 1999;353:617–622.
   PubMed Web of Science ®Google Scholar
• Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–393.
   PubMed Web of Science ®Google Scholar
• Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–591.
   PubMed Web of Science ®Google Scholar
• Vaccaro O, Franzini L, Miccoli R, et al. Feasibility and effectiveness in clinical practice of a multifactorial intervention for the reduction of cardiovascular risk in patients with type 2 diabetes: the 2-year interim analysis of the MIND.IT study: a cluster randomized trial. Diabetes Care. 2013;36:2566–2572.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia. 2013;56:686–695.
   PubMed Web of Science ®Google Scholar
• Yudkin JS, Richter B. Intensive glucose control and cardiovascular outcomes. Lancet. 2009;374:522.
   PubMed Web of Science ®Google Scholar
• Wulffele MG, Kooy A, de Zeeuw D, et al. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004;256:1–14.
   PubMed Web of Science ®Google Scholar
• Glucophage [package insert]. Princeton (NJ): Bristol-Myers Squibb Co; 2009.
   Google Scholar
• Kassem SA, Raz I. Is there evidence that oral hypoglycemic agents reduce cardiovascular morbidity or mortality? No. Diabetes Care. 2009;32(suppl 2):S337–S341.
   PubMed Web of Science ®Google Scholar
• 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.
   Web of Science ®Google Scholar
• Rodger NW. Sulfonylureas and heart disease in diabetes management. Diabetes Spectrum. 1999;12:95–97.
   Google Scholar
• Actos [package insert]. Deerfield (IL): Takeda Pharmaceuticals Inc; 2013.
   Google Scholar
• Avandia [package insert]. Research Triangle Park (NC): GlaxoSmithKline; 2013.
   Google Scholar
• Basile JN. The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular risk in patients with type 2 diabetes (T2DM). J Diabetes Complications. 2013;27:280–286.
   PubMed Web of Science ®Google Scholar
• Januvia [package insert]. Whitehouse Station (NJ): Merck & co. Inc.; 2014.
   Google Scholar
• Nesina [package insert]. Deerfield (IL): Takeda Pharmaceuticals Inc; 2013.
   Google Scholar
• Onglyza [package insert]. Wilmington (DC): AstraZeneca Pharmaceuticals LP; 2014.
   Google Scholar
• Tradjenta [package insert]. Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals, Inc; 2014.
   Google Scholar
• Choe EY, Cho Y, Choi Y, et al. The effect of DPP-4 inhibitors on metabolic parameters in patients with type 2 diabetes. Diabetes Metab J. 2014;38:211–219.
   PubMedGoogle Scholar
• Katout M, Zhu H, Rutsky J, 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;27:130–139.
   Google Scholar
• Usiskin K, Kline I, Fung A, et al. Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results. Postgrad Med. 2014;126:16–34.
   PubMed Web of Science ®Google Scholar
• Randeree HA, Omar MAK, Motala AA, et al. Effect of insulin therapy on blood pressure in NIDDM patients with secondary failure. Diabetes Care. 1992;15:1258–1263.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Weir MR, Januszewicz A, Gilbert RE, et al. 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. 2014;16:875–882.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Bianchi C, Miccoli R, Daniele G, et al. Is there evidence that oral hypoglycemic agents reduce cardiovascular morbidity/mortality? Yes. Diabetes Care. 2009;32(suppl 2):S342–S348.
   PubMed Web of Science ®Google Scholar
• Glucophage [package insert]. Princeton (NJ): Bristol-Myers Squibb Co; 2009.
   Google Scholar
• Sun F, Wu S, Wang J, 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;37:225–241.
   PubMed Web of Science ®Google Scholar
• Food and Drug Administration. Guidance for industry. Diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008 [cited 2016 January 27]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf
   Google Scholar
• Hermansen K, Baekdal TA, During M, et al. Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, cross-over trial. Diabetes Obes Metab. 2013;15:1040–1048.
   PubMed Web of Science ®Google Scholar
• Matikainen N, Manttari S, Schweizer A, et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia. 2006;49:2049–2057.
   PubMed Web of Science ®Google Scholar
• Tremblay AJ, Lamarche B, Deacon CF, et al. Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:366–373.
   PubMed Web of Science ®Google Scholar
• Abdul-Ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17:268–275.
   PubMed Web of Science ®Google Scholar
• Harrison LB, Adams-Huet B, Li X, et al. Intensive therapy in newly diagnosed type 2 diabetes – results of a 6-year randomized trial: beta-cell preservation in type 2 diabetes. J Investig Med. 2014;62:676–686.
   PubMed Web of Science ®Google Scholar
• Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinol Metab. 2015;6:19–28.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Stein P, Berg JK, Morrow L, et al. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial. Metabolism. 2014;63:1296–1303.
   PubMed Web of Science ®Google Scholar
• Kramer CK, Zinman B, Choi H, et al. The impact of chronic liraglutide therapy on glucagon secretion in type 2 diabetes: insight from the LIBRA trial. J Clin Endocrinol Metab. 2015 Jul;31:jc20152725.
   Google Scholar
• Food and Drug Adminstration Drug Safety Communication. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. 2015 Dec 4 [cited 2015 Dec 22]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm
   Google Scholar
• Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–1642.
   PubMed Web of Science ®Google Scholar
• Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015;3:8–10.
   PubMed Web of Science ®Google Scholar
• Invokana [package insert]. Titusville (NJ): Janssen Pharmaceuticals, Inc.; 2015.
   Google Scholar
• Food and Drug Adminstration Drug Safety Communication. FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. 2015 Sept 10 [cited 2015 Dec 22]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm
   Google Scholar
• Watts NB, Bilezikian JP, Usiskin K. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101:157–166.
   Google Scholar
• Bilezikian JP, Watts NB, Usiskin K. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016;101:44–51.
   Google Scholar
• Farxiga [package insert]. Princeton (NJ): Astrazeneca-us; 2015.
   Google Scholar
• ORIGIN trial investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–328.
   PubMed Web of Science ®Google Scholar
• Mellbin LG, Ryden L, Riddle MC, et al. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J. 2013;34:3137–3144.
   PubMed Web of Science ®Google Scholar
• Kim SC, Glynn RJ, Liu J, et al. Dipeptidyl peptidase-4 inhibitors do not increase the risk of cardiovascular events in type 2 diabetes: a cohort study. Acta Diabetol. 2014;51:1015–1023.
   PubMed Web of Science ®Google Scholar
• Paul SK, Klein K, Maggs D, et al. The association of the treatment with glucagon-like peptide-1 receptor agonist exenatide or insulin with cardiovascular outcomes in patients with type 2 diabetes: a retrospective observational study. Cardiovasc Diabetol. 2015;14:10.
   PubMed Web of Science ®Google Scholar
• Bentley-Lewis R, Aguilar D, Riddle MC, et al. Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J. 2015;169:631–638.
   PubMed Web of Science ®Google Scholar
• A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R) [cited 2015 Dec 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT01989754
   Google Scholar
• Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) [cited 2015 Dec 22]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02065791
   Google Scholar