Advertisement
Articles from the Incretin Hormones and Incretin-based Glucose-lowering Medications Special Issue,Edited by Michael Nauck, Manfredi Rizzo and Christos Mantzoros| Volume 104, 154045, March 01, 2020

Differential indication for SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with established atherosclerotic heart disease or at risk for congestive heart failure

Published:December 07, 2019DOI:https://doi.org/10.1016/j.metabol.2019.154045

      Highlights

      • SGLT-2 inhibitors reduce renal hard outcomes, GLP-1 receptor agonists albuminuria.
      • SGLT-2 inhibitors prevent heart failure, GLP-1 receptor agonists are neutral.
      • GLP-1 receptor agonists have a beneficial “metabolo-anti-atherosclerotic” profile.
      • SGLT-2 inhibitors exert their protective role with a “metabolo-diuretic” profile.

      Abstract

      SGLT-2 inhibitors and most GLP-1 receptor agonists demonstrated cardiovascular superiority and reduction of cardiovascular and overall mortality. These results stand as a turning point in the management of diabetes, shifting the focus from controlling glucose levels to mastering the extra-glycemic effects of these new drugs. This narrative review will discuss recent CVOT with focus on SGLT-2 inhibitors and GLP-1 receptor agonists to distinguish relevant patients' characteristics as potential predictors for therapeutic efficacy. It will also examine their efficacy and safety, the differences in their cardiovascular and renal benefits, aiming to convey clinical suggestions for everyday practice.

      Abbreviations:

      SGLT-2 (Sodium-glucose costransporter-2), GLP-1 (Glucagon-like peptide-1), CVOT (Cardiovascular outcome trials), LDL-C (LDL cholesterol), DPP-4 (Dipeptidyl peptidase-4), ADA (American Diabetes Association), EASD (European Association for the Study of Diabetes), MACE (Major adverse cardiovascular events), CKD (Chronic kidney disease), RAAS (Renin-angiotensin-aldosterone system), HFrEF (Heart failure with reduced ejection fraction), LEA (Lower extremity amputation), RCT (Randomized controlled trials), FDA (Food and Drug Administration), EMA (European Medicines Agencies), DKA (Diabetic ketoacidosis), FBG (Fasting blood glucose), NASH (Non-alcoholic steatohepatitis), FFA (Free fatty acids), hsCRP (high sensitivity C-reactive protein), cIMT (Carotid intima-media thickness), GLP-1/GCG (Glucagon-like peptide-1/Glucagon), GLP-1/GIP (glucagon-like peptide-1/glucose-dependent insulinotropic polypetide), ERA-EDTA (European Renal Association-European Dialysis and Transplant Association)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Metabolism - Clinical and Experimental
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rawshani A
        • Rawshani A
        • Franzén S
        • Sattar N
        • Eliasson B
        • Svensson A-M
        • et al.
        Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2018; 379: 633-644https://doi.org/10.1056/nejmoa1800256
        • Gæde P
        • Lund-Andersen H
        • Parving H-H
        • Pedersen O
        Effect of a multifactorial intervention on mortality in type 2 diabetes.
        N Engl J Med. 2008; 358: 580-591https://doi.org/10.1056/nejmoa0706245
        • Cefalu WT
        • Kaul S
        • Gerstein HC
        • Holman RR
        • Zinman B
        • Skyler JS
        • et al.
        Cardiovascular outcomes trials in type 2 diabetes: where do we go from Here? Ref lections from a diabetes care Editors’ expert forum.
        Diabetes Care. 2018; 41: 14-31https://doi.org/10.2337/dci17-0057
      1. Riddle MC, Bakris G, Blonde L, Boulton AJM, D ‘alessio D, De Groot M, et al. Standard medical care in diabetes 2018. Diabetes Care 2018;41. doi:https://doi.org/10.2337/dc18-Sint01.

        • The Action to Control Cardiovascular Risk in Diabetes Study Group
        Effect of intensive glucose lowering in type 2 diabetes.
        N Engl J Med. 2008; 358: 2545-2559
        • The ADVANCE Collaborative Group
        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
        • Reda D
        • Ph D
        • Emanuele N
        • et al.
        Glucose control and vascular complications in veterans with type 2 diabetes.
        N Engl J Med. 2009; 360: 129-139
      2. Reaven PD, Emanuele N V., Wiitala WL, Bahn GD, Reda DJ, McCarren M, et al. Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up. N Engl J Med 2019;380:2215–24. doi:https://doi.org/10.1056/NEJMoa1806802.

        • Giorgino F
        • Home PD
        • Tuomilehto J
        Glucose control and vascular outcomes in type 2 diabetes: is the picture clear?.
        Diabetes Care. 2016; 39: S187-S195https://doi.org/10.2337/dcS15-3023
        • Marso SP
        • Daniels GH
        • Brown-Frandsen K
        • Kristensen P
        • Mann JFE
        • Nauck MA
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2016; 375: 311-322https://doi.org/10.1056/NEJMoa1603827
      3. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834–44. doi:https://doi.org/10.1056/NEJMoa1607141.

        • Holman RR
        • Bethel MA
        • Mentz RJ
        • Thompson VP
        • Lokhnygina Y
        • Buse JB
        • et al.
        Effects of once-weekly Exenatide on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 1228-1239https://doi.org/10.1056/NEJMoa1612917
        • Hernandez AF
        • Green JB
        • Janmohamed S
        • D’Agostino RB
        • Granger CB
        • Jones NP
        • et al.
        Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony outcomes): a double-blind, randomised placebo-controlled trial.
        Lancet. 2018; 392: 1519-1529https://doi.org/10.1016/S0140-6736(18)32261-X
        • Pfeffer MA
        • Claggett B
        • Diaz R
        • Dickstein K
        • Gerstein HC
        • Køber LV
        • et al.
        Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        N Engl J Med. 2015; 373: 2247-2257https://doi.org/10.1056/NEJMoa1509225
      4. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394(10193):121–130. doi: https://doi.org/10.1016/S0140-6736(19)31149-3.

      5. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2019;381(9):841–851. doi:https://doi.org/10.1056/NEJMoa1901118.

        • Zinman B
        • Wanner C
        • Lachin JM
        • Fitchett D
        • Bluhmki E
        • Hantel S
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128https://doi.org/10.1056/NEJMoa1504720
        • Neal B
        • Perkovic V
        • Mahaffey KW
        • de Zeeuw D
        • Fulcher G
        • Erondu N
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657https://doi.org/10.1056/NEJMoa1611925
      6. Wiviott S, Raz I, Bonaca M, Mosenzon O, Kato E, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019;380:347–57. doi:https://doi.org/10.1056/NEJMoa1812389.

      7. Davies MJ, Alessio DAD, Fradkin J, Kernan WN, Mathieu C. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018. doi:https://doi.org/10.1007/s00125-018-4729-5.

        • Consoli A
        • Formoso G
        • Baldassarre MPA
        • Febo F
        A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment.
        Expert Opin Drug Saf. 2018; 17: 293-302https://doi.org/10.1080/14740338.2018.1428305
        • Wanner C
        • Inzucchi SE
        • Lachin JM
        • Fitchett D
        • von Eynatten M
        • Mattheus M
        • et al.
        Empagliflozin and progression of kidney disease in type 2 diabetes.
        N Engl J Med. 2016; 375: 323-334https://doi.org/10.1056/nejmoa1515920
      8. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019;380(24):2295–2306. doi:https://doi.org/10.1056/NEJMoa1811744.

      9. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. doi:https://doi.org/10.1016/S0140-6736(18)32590-X.

        • Eng J
        • Kleinman WA
        • Singh L
        • Singh G
        • Raufman JP
        Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom: further evidence for an exendin receptor on dispersed acini from Guinea pig pancreas.
        J Biol Chem. 1992; 267: 7402-7405
        • Caruso I
        • Cignarelli A
        • Giorgino F
        Heterogeneity and similarities in GLP-1 receptor agonists cardiovascular outcome trials.
        Trends Endocrinol Metab. 2019; 30: 578-589https://doi.org/10.1016/j.tem.2019.07.004
        • Mann JFE
        • Ørsted DD
        • Brown-Frandsen K
        • Marso SP
        • Poulter NR
        • Rasmussen S
        • et al.
        Liraglutide and renal outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 839-848https://doi.org/10.1056/nejmoa1616011
      10. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 2019;6736:1–8. doi:https://doi.org/10.1016/S0140-6736(19)31150-X.

        • Verma S
        • Bhatt DL
        • Bain SC
        • Buse JB
        • Mann JFE
        • Marso SP
        • et al.
        Effect of liraglutide on cardiovascular events in patients with type 2 diabetes mellitus and polyvascular disease.
        Results of the LEADER Trial Circulation. 2018; 137: 2179-2183https://doi.org/10.1161/CIRCULATIONAHA.118.033898
        • Verma S
        • Poulter NR
        • Bhatt DL
        • Bain SC
        • Buse JB
        • Leiter LA
        • et al.
        Effects of Liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke.
        Circulation. 2018; 138: 2884-2894https://doi.org/10.1161/circulationaha.118.034516
        • Marx N
        • Libby P
        Cardiovascular benefits of GLP-1 receptor Agonism: is inflammation a key?.
        JACC Basic to Transl Sci. 2018; 3: 858-860https://doi.org/10.1016/j.jacbts.2018.11.008
      11. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab 2016:737–49. doi:i:https://doi.org/10.1111/dom.12670.

        • Heerspink HJL
        • Perkins BA
        • Fitchett DH
        • Husain M
        • Cherney DZI
        Sodium glucose Cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.
        Circulation. 2016; 134: 752-772https://doi.org/10.1161/CIRCULATIONAHA.116.021887
        • Kawanami D
        • Matoba K
        • Takeda Y
        • Nagai Y
        • Akamine T
        • Yokota T
        • et al.
        SGLT2 inhibitors as a therapeutic option for diabetic nephropathy.
        Int J Mol Sci. 2017; 18https://doi.org/10.3390/ijms18051083
      12. Van Baar MJB, Van Ruiten CC, Muskiet MHA, Van Bloemendaal L, IJzerman RG, Van Raalte DH. SGLT2 inhibitors in combination therapy: From mechanisms to clinical considerations in type 2 diabetes management. Diabetes Care 2018;41:1543–56. doi:https://doi.org/10.2337/dc18-0588

      13. Lee JY, Cho Y, Lee M, Kim YJ, Lee YH, Lee BW, et al. Predictors of the therapeutic efficacy and consideration of the best combination therapy of sodium-glucose co-transporter 2 inhibitors. Diabetes Metab J 2019;43:158–73. doi:https://doi.org/10.4093/dmj.2018.0057.

        • Kelly MS
        • Lewis J
        • Huntsberry AM
        • Dea L
        • Portillo I
        Efficacy and renal outcomes of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease.
        Postgrad Med. 2019; 131: 31-42https://doi.org/10.1080/00325481.2019.1549459
        • Thomas MC
        • Cherney DZI
        The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure.
        Diabetologia. 2018; 61: 2098-2107https://doi.org/10.1007/s00125-018-4669-0
        • Fioretto P
        • Del Prato S
        • Buse JB
        • Goldenberg R
        • Giorgino F
        • Reyner D
        • et al.
        Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): the DERIVE study.
        Diabetes Obes Metab. 2018; 20: 2532-2540https://doi.org/10.1111/dom.13413
        • Brown E
        • Wilding JPH
        • Barber TM
        • Alam U
        • Cuthbertson DJ
        Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: mechanistic possibilities.
        Obes Rev. 2019; 20: 816-828https://doi.org/10.1111/obr.12841
        • Cai X
        • Yang W
        • Gao X
        • Chen Y
        • Zhou L
        • Zhang S
        • et al.
        The association between the dosage of SGLT2 inhibitor and weight reduction in type 2 diabetes patients: a meta-analysis.
        Obesity. 2018; 26: 70-80https://doi.org/10.1002/oby.2206
        • 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: 429-430https://doi.org/10.2337/dc14-1596
        • Tikkanen I
        • Narko K
        • Zeller C
        • Green A
        • Salsali A
        • Broedl UC
        • et al.
        Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension.
        Diabetes Care. 2015; 38: 420-428https://doi.org/10.2337/dc14-1096
        • Wanner C
        • Lachin JM
        • Inzucchi SE
        • Fitchett D
        • Mattheus M
        • George J
        • et al.
        Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease.
        And Chronic Kidney Disease Circulation. 2018; 137: 119-129https://doi.org/10.1161/CIRCULATIONAHA.117.028268
        • DeFronzo RA
        • Norton L
        • Abdul-Ghani M
        Renal, metabolic and cardiovascular considerations of SGLT2 inhibition.
        Nat Rev Nephrol. 2017; 13: 11-26https://doi.org/10.1038/nrneph.2016.170
        • Mudaliar S
        • Alloju S
        • Henry RR
        Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis.
        Diabetes Care. 2016; 39: 1115-1122https://doi.org/10.2337/dc16-0542
        • Delanaye P
        • Scheen AJ
        Preventing and treating kidney disease in patients with type 2 diabetes.
        Expert Opin Pharmacother. 2019; 20: 277-294https://doi.org/10.1080/14656566.2018.1551362
      14. Zelniker TA, Wiviott SD, Raz I, Im KA, Goodrich EL, Furtado RHM, et al. Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus. Circulation 2019;139:2022–31. doi:https://doi.org/10.1161/CIRCULATIONAHA.118.038868.

        • Cherney DZI
        • Odutayo A
        • Verma S
        A big win for diabetic kidney disease: CREDENCE.
        Cell Metab. 2019; 29: 1024-1027https://doi.org/10.1016/j.cmet.2019.04.011
        • Barutta F
        • Bernardi S
        • Gargiulo G
        • Durazzo M
        • Gruden G
        SGLT2 inhibition to address the unmet needs in diabetic nephropathy.
        Diabetes Metab Res Rev. 2019; 35e3171https://doi.org/10.1002/dmrr.3171
        • Verma S
        • Jüni P
        • Mazer CD
        Pump, pipes, and filter: do SGLT2 inhibitors cover it all?.
        Lancet. 2019; 393: 3-5https://doi.org/10.1016/S0140-6736(18)32824-1
        • Maack C
        • Lehrke M
        Backs J, Heinzel FR, Hulot JS, Marx N, et al. heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the translational research Committee of the Heart Failure Association-European Society of cardiology.
        Eur Heart J. 2018; 39: 4243-4254https://doi.org/10.1093/eurheartj/ehy596
        • Ferrannini E
        • Mark M
        • Mayoux E
        CV protection in the EMPA-REG OUTCOME trial: a thrifty substrate hypothesis.
        Diabetes Care. 2016; 39: 1108-1114https://doi.org/10.2337/dc16-0330
      15. Nielsen R, Møller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, et al. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation 2019;139:2129–41. doi:https://doi.org/10.1161/CIRCULATIONAHA.118.036459.

      16. Horton JL, Davidson MT, Kurishima C, Vega RB, Powers JC, Matsuura TR, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight 2019;4:1–19. doi:https://doi.org/10.1172/jci.insight.124079.

      17. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, et al. Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics. J Am Coll Cardiol 2019;73:1931 LP – 1944. doi:https://doi.org/10.1016/j.jacc.2019.01.056.

        • Kappel BA
        • Lehrke M
        • Schütt K
        • Artati A
        • Adamski J
        • Lebherz C
        • et al.
        Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease.
        Circulation. 2017; 136: 969-972https://doi.org/10.1161/CIRCULATIONAHA.117.029166
        • Verma S
        • McMurray JJV
        SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.
        Diabetologia. 2018; 61: 2108-2117https://doi.org/10.1007/s00125-018-4670-7
      18. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, et al. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation 2019;139:2528–36. doi:https://doi.org/10.1161/CIRCULATIONAHA.119.040130.

        • Fitchett D
        • Zinman B
        • Wanner C
        • Lachin JM
        • Hantel S
        • Salsali A
        • et al.
        Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial.
        Eur Heart J. 2016; 37: 1526-1534https://doi.org/10.1093/eurheartj/ehv728
      19. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019:1–13. doi:https://doi.org/10.1056/nejmoa1911303.

        • Anastasilakis AD
        • Sternthal E
        • Mantzoros CS
        Beyond glycemic control: new guidance on cardio-renal protection.
        Metabolism. 2019; 99: 113-115https://doi.org/10.1016/j.metabol.2019.02.004
      20. Ueda P, Svanström H, Melbye M, Eliasson B, Svensson A-M, Franzén S, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ 2018;363:k4365. doi:https://doi.org/10.1136/bmj.k4365.

      21. Katsiki N, Dimitriadis G, Hahalis G, Papanas N, Tentolouris N, Triposkiadis F, et al. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) use and risk of amputation: an expert panel overview of the evidence. Metabolism 2019;96:92–100. doi:https://doi.org/10.1016/j.metabol.2019.04.008.

        • Kohler S
        • Zeller C
        • Iliev H
        • Kaspers S
        Safety and tolerability of empagliflozin in east Asian patients with type 2 diabetes: pooled analysis of phase I–III clinical trials.
        Adv Ther. 2017; 34: 1707-1726https://doi.org/10.1007/s12325-017-0573-0
        • Sung J
        • Padmanabhan S
        • Gurung S
        • Inglis S
        • Vicaretti M
        • Begg L
        • et al.
        SGLT2 inhibitors and amputation risk: Real-world data from a diabetes foot wound clinic.
        J Clin Transl Endocrinol. 2018; 13: 46-47https://doi.org/10.1016/j.jcte.2018.07.002
        • Silwal P
        • Kim JK
        • Yuk JM
        • Jo EK
        AMP-activated protein kinase and host defense against infection.
        Int J Mol Sci. 2018; 19https://doi.org/10.3390/ijms19113495
        • Sherman SE
        • Bell GI
        • Teoh H
        • Al-Omran M
        • Connelly KA
        • Bhatt DL
        • et al.
        Canagliflozin improves the recovery of blood flow in an experimental model of severe limb ischemia.
        JACC Basic to Transl Sci. 2018; 3: 327-329https://doi.org/10.1016/j.jacbts.2018.01.010
        • Scheen AJ
        An update on SGLT2 inhibitors safety.
        Expert Opin Drug Saf. 2019; 18: 295-311https://doi.org/10.1080/14740338.2019.1602116
        • Azharuddin M
        • Adil M
        • Ghosh P
        • Sharma M
        Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: a systematic literature review and Bayesian network meta-analysis of randomized controlled trials.
        Diabetes Res Clin Pract. 2018; 146: 180-190https://doi.org/10.1016/j.diabres.2018.10.019
        • Fralick M
        • Kim SC
        • Schneeweiss S
        • Kim D
        • Redelmeier DA
        • Patorno E
        Fracture risk after initiation of use of Canagliflozin: a cohort study.
        Ann Intern Med. 2019; 170: 155-163https://doi.org/10.7326/M18-0567
        • Puckrin R
        • Saltiel MP
        • Reynier P
        • Azoulay L
        • Yu OHY
        • Filion KB
        SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials.
        Acta Diabetol. 2018; 55: 503-514https://doi.org/10.1007/s00592-018-1116-0
        • Thong KY
        • Yadagiri M
        • Barnes DJ
        • Morris DS
        • Chowdhury TA
        • Chuah LL
        • et al.
        Clinical risk factors predicting genital fungal infections with sodium–glucose cotransporter 2 inhibitor treatment: the ABCD nationwide dapagliflozin audit.
        Prim Care Diabetes. 2018; 12: 45-50https://doi.org/10.1016/j.pcd.2017.06.004
        • 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: 524-536https://doi.org/10.1111/dom.12849
        • Gentilella R
        • Pechtner V
        • Corcos A
        • Consoli A
        Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same?.
        Diabetes Metab Res Rev. 2019; 35e3070https://doi.org/10.1002/dmrr.3070
        • Sorli C
        • Harashima S
        • Tsoukas G
        • Unger J
        • Karsbøl J
        • Hansen T
        • et al.
        Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
        Lancet Diabetes Endocrinol. 2017; : 251-260https://doi.org/10.1016/S2213-8587(17)30013-X
        • Hedrington MS
        • Davis SN
        Oral semaglutide for the treatment of type 2 diabetes Oral semaglutide for the treatment of type 2 diabetes.
        Expert Opin Pharmacother. 2018; : 1-9https://doi.org/10.1080/14656566.2018.1552258
        • Lorenzi M
        • Ploug UJ
        • Langer J
        • Skovgaard R
        • Zoratti M
        • Jansen J
        Liraglutide versus SGLT-2 inhibitors in people with type 2 diabetes: a network meta-analysis.
        Diabetes Ther. 2017; 8: 85-99https://doi.org/10.1007/s13300-016-0217-4
      22. Babenko AY, Savitskaya DA, Kononova YA, Trofimova AY, Simanenkova A V., Vasilyeva EY, et al. Predictors of effectiveness of glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes and obesity. J Diabetes Res 2019;15:22–30. doi:10.14341/omet9584.

      23. Aroda VR, Ahmann A, Cariou B, Chow F, Davies MJ, Jódar E, et al. Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1–7 trials. Diabetes Metab 2019;45(5):409–418. doi:https://doi.org/10.1016/j.diabet.2018.12.001.

      24. Mata-Cases M, Franch-Nadal J, Ortega E, Real J, Gratacòs M, Vlacho B, et al. Glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: real-world evidence from a Mediterranean area. Curr Med Res Opin 2019;35(10):1735–1744. doi:https://doi.org/10.1080/03007995.2019.1618806.

        • DeFronzo RA
        • Stonehouse AH
        • Han J
        • Wintle ME
        Relationship of baseline HbA 1c and efficacy of current glucose-lowering therapies: a meta-analysis of randomized clinical trials.
        Diabet Med. 2010; 27: 309-317https://doi.org/10.1111/j.1464-5491.2010.02941.x
      25. Usui R, Sakuramachi Y, Seino Y, Murotani K, Kuwata H, Tatsuoka H, et al. Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining β-cell function and the achievement of the glycated hemoglobin target 1 year after initiation. J Diabetes Investig 2018;9:822–30. doi:https://doi.org/10.1111/jdi.12773.

        • Jones AG
        • McDonald TJ
        • Shields BM
        • Hill AV
        • Hyde CJ
        • Knight BA
        • et al.
        Markers of β-cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes.
        Diabetes Care. 2016; 39: 250-257https://doi.org/10.2337/dc15-0258
      26. Heo CU, Choi C-I. Current Progress in Pharmacogenetics of Second-Line Antidiabetic Medications: Towards Precision Medicine for Type 2 Diabetes. J Clin Med 2019;8(3). doi:https://doi.org/10.3390/jcm8030393.

        • Mehta A
        • Marso SP
        • Neeland IJ
        Liraglutide for weight management: a critical review of the evidence.
        Obes Sci Pract. 2017; 3: 3-14https://doi.org/10.1002/osp4.84
        • Christou GA
        • Katsiki N
        • Blundell J
        • Fruhbeck G
        • Kiortsis DN
        Semaglutide as a promising antiobesity drug.
        Obes Rev. 2019; 20: 805-815https://doi.org/10.1111/obr.12839
        • Maloney A
        • Rosenstock J
        • Fonseca V
        A model-based meta-analysis of 24 Antihyperglycemic drugs for type 2 diabetes: comparison of treatment effects at therapeutic doses.
        Clin Pharmacol Ther. 2019; 105: 1213-1223https://doi.org/10.1002/cpt.1307
        • Drucker DJ
        The ascending GLP-1 road from clinical safety to reduction of cardiovascular complications.
        Diabetes. 2018; 67: 1710-1719https://doi.org/10.2337/dbi18-0008
        • Ranjbar G
        • Mikhailidis DP
        • Sahebkar A
        Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: think out of the box!.
        Metabolism. 2019; 101: 154001https://doi.org/10.1016/j.metabol.2019.154001
        • Armstrong MJ
        • Gaunt P
        • Aithal GP
        • Barton D
        • Hull D
        • Parker R
        • et al.
        Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
        Lancet. 2016; 387: 679-690https://doi.org/10.1016/S0140-6736(15)00803-X
        • Rizzo M
        • Nikolic D
        • Patti AM
        • Mannina C
        • Montalto G
        • McAdams BS
        • et al.
        GLP-1 receptor agonists and reduction of cardiometabolic risk: potential underlying mechanisms.
        Biochim Biophys Acta Mol Basis Dis. 2018; 1864: 2814-2821https://doi.org/10.1016/j.bbadis.2018.05.012
        • Song X
        • Jia H
        • Jiang Y
        • Wang L
        • Zhang Y
        • Mu Y
        • et al.
        Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 diabetes mellitus: a meta-analysis.
        Sci Rep. 2015; 5: 1-8https://doi.org/10.1038/srep10202
        • Almutairi M
        • Al Batran R
        • Ussher JR
        Glucagon-like peptide-1 receptor action in the vasculature.
        Peptides. 2019; 111: 26-32https://doi.org/10.1016/j.peptides.2018.09.002
        • Gaspari T
        • Welungoda I
        • Widdop RE
        • Simpson RW
        • Dear AE
        The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE−/− mouse model.
        Diabetes Vasc Dis Res. 2013; 10: 353-360https://doi.org/10.1177/1479164113481817
        • Tashiro Y
        • Sato K
        • Watanabe T
        • Nohtomi K
        • Terasaki M
        • Nagashima M
        • et al.
        A glucagon-like peptide-1 analog liraglutide suppresses macrophage foam cell formation and atherosclerosis.
        Peptides. 2014; 54: 19-26https://doi.org/10.1016/j.peptides.2013.12.015
        • Rizzo M
        • Rizvi AA
        • Patti AM
        • Nikolic D
        • Giglio RV
        • Castellino G
        • et al.
        Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study.
        Cardiovasc Diabetol. 2016; 15: 1-8https://doi.org/10.1186/s12933-016-0480-8
        • Verma S
        • Leiter LA
        • Mazer CD
        • Bain SC
        • Buse J
        • Marso S
        • et al.
        Liraglutide reduces cardiovascular events and mortality in type 2 diabetes mellitus independently of baseline low-density lipoprotein cholesterol levels and statin use.
        Circulation. 2018; 138: 1605-1607https://doi.org/10.1161/CIRCULATIONAHA.118.036862
        • Del Olmo-Garcia MI
        • Merino-Torres JF
        GLP-1 receptor agonists and cardiovascular disease in patients with type 2 diabetes.
        J Diabetes Res. 2018; 2018: 1-12https://doi.org/10.1155/2018/4020492
        • Tuttle KR
        • McKinney TD
        • Davidson JA
        • Anglin G
        • Harper KD
        • Botros FT
        Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials.
        Diabetes Obes Metab. 2017; 19: 436-441https://doi.org/10.1111/dom.12816
        • Tuttle KR
        • Lakshmanan MC
        • Rayner B
        • Busch RS
        • Zimmermann AG
        • Woodward DB
        • et al.
        Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label.
        Randomised Trial Lancet Diabetes Endocrinol. 2018; 6: 605-617https://doi.org/10.1016/S2213-8587(18)30104-9
      27. Thomas MC. The potential and pitfalls of GLP-1 receptor agonists for renal protection in type 2 diabetes. Diabetes Metab. 2017;43 Suppl 1:2S20-2S27. doi: https://doi.org/10.1016/S1262-3636(17)30069-1.

        • Nauck MA
        • Meier JJ
        • Cavender MA
        • El Aziz MA
        • Drucker DJ
        Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.
        Circulation. 2017; 136: 849-870https://doi.org/10.1161/CIRCULATIONAHA.117.028136
        • Lønborg J
        • Vejlstrup N
        • Kelbæk H
        • Bøtker HE
        • Kim WY
        • Mathiasen AB
        • et al.
        Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction.
        Eur Heart J. 2011; 33: 1491-1499https://doi.org/10.1093/eurheartj/ehr309
        • Nauck MA
        • Tornøe K
        • Rasmussen S
        • Treppendahl MB
        • Marso SP
        Cardiovascular outcomes in patients who experienced a myocardial infarction while treated with liraglutide versus placebo in the LEADER trial.
        Diabetes Vasc Dis Res. 2018; 15: 465-468https://doi.org/10.1177/1479164118783935
        • Kristensen SL
        • Rorth R
        • Jhund PS
        • Docherty KF
        • Sattar N
        • Preiss D
        • et al.
        Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
        Lancet Diabetes Endocrinol. 2019; 7: 776-785
        • Margulies KB
        • Hernandez AF
        • Redfield MM
        • Givertz MM
        • Oliveira GH
        • Cole R
        • et al.
        Effects of Liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial.
        JAMA. 2016; 316: 500-508https://doi.org/10.1001/jama.2016.10260
      28. Lepore JJ, Olson E, Demopoulos L, Haws T, Fang Z, Barbour AM, et al. Effects of the Novel Long-Acting GLP-1 Agonist, Albiglutide, on Cardiac Function, Cardiac Metabolism, and Exercise Capacity in Patients With Chronic Heart Failure and Reduced Ejection Fraction. JACC Hear Fail 2016;4:559–66. doi:10.1016/j.jchf.2016.01.008.

        • Sikirica MV
        • Martin AA
        • Wood R
        • Leith A
        • Piercy J
        • Higgins V
        Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes.
        Diabetes Metab Syndr Obes Targets Ther. 2017; 10: 403-412https://doi.org/10.2147/DMSO.S141235
        • Pilla SJ
        • Segal JB
        • Alexander GC
        • Boyd CM
        • Maruthur NM
        Differences in National Diabetes Treatment Patterns and trends between older and younger adults Scott.
        J Am Geriatr Soc. 2019; 67: 1066-1073https://doi.org/10.1111/jgs.15790
      29. Gilbert M, Bain S, Franek E, Jodar-Gimeno E, Nauck M, Pratley R, et al. Annals of Internal Medicine Effect of Liraglutide on Cardiovascular Outcomes in Elderly. Ann Intern Med 2019;170(6):423–426. doi:https://doi.org/10.7326/M18-1569.

        • Boustani MA
        • Pittman I
        • Yu M
        • Thieu VT
        • Varnado OJ
        • Juneja R
        Similar efficacy and safety of once-weekly dulaglutide in patients with type 2 diabetes aged ≥65 and <65 years.
        Diabetes Obes Metab. 2016; 18: 820-828https://doi.org/10.1111/dom.12687
        • Luo G
        • Liu H
        • Lu H
        Glucagon-like peptide-1(GLP-1) receptor agonists: potential to reduce fracture risk in diabetic patients?.
        Br J Clin Pharmacol. 2016; 81: 78-88https://doi.org/10.1111/bcp.12777
        • Dhatariya K
        • Bain SC
        • Buse JB
        • Simpson R
        • Tarnow L
        • Kaltoft MS
        • et al.
        The impact of liraglutide on diabetes-related foot ulceration and associated complications in patients with type 2 diabetes at high risk for cardiovascular events: results from the LEADER trial.
        Diabetes Care. 2018; 41: 2229-2235https://doi.org/10.2337/dc18-1094
        • Abdelgadir E
        • Rashid F
        • Bashier A
        • Ali R
        SGLT-2 inhibitors and cardiovascular protection: lessons and gaps in understanding the current outcome trials and possible benefits of combining SGLT-2 inhibitors with GLP-1 agonists.
        J Clin Med Res. 2018; 10: 615-625https://doi.org/10.14740/jocmr3467w
        • Bonnet F
        • Scheen AJ
        Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: the potential contribution to diabetes complications and cardiovascular disease.
        Diabetes Metab. 2018; 44: 457-464https://doi.org/10.1016/j.diabet.2018.09.005
        • Shigiyama F
        • Kumashiro N
        • Miyagi M
        • Ikehara K
        • Kanda E
        • Uchino H
        • et al.
        Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study.
        Cardiovasc Diabetol. 2017; 16: 1-12https://doi.org/10.1186/s12933-017-0564-0
        • Leng W
        • Ouyang X
        • Lei X
        • Wu M
        • Chen L
        • Wu Q
        • et al.
        The SGLT-2 inhibitor Dapagliflozin has a therapeutic effect on atherosclerosis in diabetic ApoE −/− mice.
        Mediators Inflamm. 2016; 2016: 1-13https://doi.org/10.1155/2016/6305735
        • 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: 939-940https://doi.org/10.1001/jamacardio.2017.1891