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Glycemic efficacy and safety of glucagon-like peptide-1 receptor agonist on top of sodium-glucose co-transporter-2 inhibitor treatment compared to sodium-glucose co-transporter-2 inhibitor alone: A systematic review and meta-analysis of randomized controlled trials

Published:November 13, 2019DOI:https://doi.org/10.1016/j.diabres.2019.107927

      Abstract

      Objective

      Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now considered as key players in the treatment of type 2 diabetes mellitus (T2DM). The purpose of this meta-analysis was to provide precise effect estimates regarding the safety and efficacy of the addition of a GLP-1RA on top of SGLT-2i treatment.

      Research design and methods

      PubMed and CENTRAL, along with grey literature sources, were searched from their inception to May 2019 for randomized controlled trials (RCTs) with a duration ≥ 12 weeks, evaluating the safety and efficacy of addition of a GLP-1RA on a SGLT-2i compared to SGLT-2i alone in patients with T2DM. We also used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the credibility of our summary estimates.

      Results

      We identified three eligible RCTs, pooling data retrieved from 1,042 patients with T2DM in total. Administration of the maximum dose of a GLP-1RA on top of SGLT-2i treatment compared to SGLT-2i alone resulted in significant decrease in HbA1c by 0.91% (95% CI; −1.41 to −0.42) [GRADE: moderate], in body weight by 1.95 kg (95% CI; −3.83 to −0.07) [GRADE: moderate], in fasting plasma glucose by 1.53 mmol/L (95% CI; −2.17 to −0.88) [GRADE: moderate] and in systolic blood pressure levels by 3.64 mm Hg (95% CI −6.24 to −1.03). No significant effects on lipid profile and diastolic blood pressure were demonstrated. A significant increase in the risk for any hypoglycemia (RR: 2.62, 95% CI; 1.15–5.96, I2 = 33%) [GRADE: moderate] and for nausea (RR: 3.21, 95% CI; 1.36–7.54, I2 = 63%) [GRADE: moderate] and a non-significant increase in the risk for diarrhoea (RR: 1.64, 95% CI; 0.98–2.75, I2 = 0%) [GRADE: low] were documented. No other safety issues were identified.

      Conclusions

      This meta-analysis suggests that a GLP-1RA/SGLT-2i combination, if tolerated, exerts significant beneficial effects on glycemic control and body weight loss, however increasing the risk for any hypoglycemia and gastrointestinal adverse events.

      Keywords

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      References

      1. Centers for disease control and prevention. National diabetes statistics report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2017.

        • Unnikrishnan R.
        • Pradeepa R.
        • Joshi S.R.
        • et al.
        Type 2 diabetes: demystifying the global epidemic.
        Diabetes. 2017; 66: 1432-1442
        • Fox C.S.
        • Golden S.H.
        • Anderson C.
        • et al.
        Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association.
        Circulation. 2015; 132: 691-718
        • Einarson T.R.
        • Acs A.
        • Ludwig C.
        • Panton U.H.
        Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017.
        Cardiovasc Diabetol. 2018; 17: 83
        • Shah A.D.
        • Langenberg C.
        • Rapsomaniki E.
        • et al.
        Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people.
        Lancet Diabetes Endocrinol. 2015; 3: 105-113
        • Patoulias Dimitrios
        • Stavropoulos Konstantinos
        • Imprialos Konstantinos
        • Athyros Vasilios
        • Doumas Michael
        • Karagiannis Asterios
        Pharmacological management of cardiac disease in patients with type 2 diabetes: Insights into clinical practice.
        CVP. 2019; 17https://doi.org/10.2174/1570161117666190426162746
        • Tancredi M.
        • Rosengren A.
        • Svensson A.M.
        • et al.
        Excess mortality among persons with type 2 diabetes.
        N Engl J Med. 2015; 373: 1720-1732
        • Franssens B.T.
        • van der Graaf Y.
        • Kappelle L.J.
        • et al.
        Body weight, metabolic dysfunction, and risk of type 2 diabetes in patients at high risk for cardiovascular events or with manifest cardiovascular disease: a cohort study.
        Diabetes Care. 2015; 38: 1945-1951
        • Abdul-Ghani M.
        • Del Prato S.
        • Chilton R.
        • DeFronzo R.A.
        SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study.
        Diabetes Care. 2016; 39: 717-725
        • Dupre J.
        Glycaemic effects of incretins in Type 1 diabetes mellitus: a concise review, with emphasis on studies in humans.
        Regul Pept. 2005; 128: 149-157
        • Lovshin J.A.
        • Drucker D.J.
        Incretin-based therapies for type 2 diabetes mellitus.
        Nat Rev Endocrinol. 2009; 5: 262-269
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2016; 375: 311-322
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2016; 375: 1834-1844
        • Hernandez A.F.
        • Green J.B.
        • Janmohamed S.
        • 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: 1519-1529
        • Wanner C.
        • Inzucchi S.E.
        • Lachin J.M.
        • et al.
        Empagliflozin and progression of kidney disease in type 2 diabetes.
        N Engl J Med. 2016; 375: 323-334
        • Perkovic V.
        • de Zeeuw D.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.
        Lancet Diabetes Endocrinol. 2018; 6: 691-704
        • Perkovic V.
        • Jardine M.J.
        • Neal B.
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
        N Engl J Med. 2019; 380: 2295-2306
        • Mann J.F.E.
        • Ørsted D.D.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and renal outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 839-848
        • Davies M.J.
        • D'Alessio D.A.
        • Fradkin J.
        • et al.
        Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
        Diabetes Care. 2018; 2018: 2669-2701
      2. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42: S103–S123.

        • Sarafidis P.
        • Ferro C.J.
        • Morales E.
        • et al.
        SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the EURECA-m and the DIABESITY working groups of the ERA-EDTA.
        Nephrol Dial Transplant. 2019; 34: 208-230
        • Goncalves E.
        • Bell D.S.H.
        Combination treatment of SGLT2 inhibitors and GLP-1 receptor agonists: symbiotic effects on metabolism and cardiorenal risk.
        Diabetes Ther. 2018; 9: 919-926
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ. 2009; 339 (b2535)
        • McGowan J.
        • Sampson M.
        • Salzwedel D.M.
        • Cogo E.
        • Foerster V.
        • Lefebvre C.
        PRESS peer review of electronic search strategies: 2015 guideline statement.
        J Clin Epidemiol. 2016; 75: 40-46
        • Higgins J.P.T.
        • Sterne J.A.C.
        • Savović J.
        • et al.
        A revised tool for assessing risk of bias in randomized trials.
        Cochrane Database Syst Rev. 2016; 10: 29-31
        • Wan X.
        • Wang W.
        • Liu J.
        • Tong T.
        Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range.
        BMC Med Res Methodol. 2014; 14: 135
        • Davies H.T.
        • Crombie I.K.
        • Tavakoli M.
        When can odds ratios mislead?.
        BMJ. 1998; 316: 989-991
      3. Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analyzing data and undertaking meta-analyses. In: Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011], The Cochrane Collaboration; 2011.

        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
      4. Review Manager (RevMan) [Computer program] Version [5.3] Copenhagen: The Nordic Cochrane Centre TCC; 2014.

      5. Schünemann HBJ, Guyatt G, Oxman A. GRADE handbook for grading quality of evidence and strength of recommendations (Updated October 2013) The GRADE Working Group; 2013.

        • Ludvik B.
        • Frias J.P.
        • Tinahones F.J.
        • et al.
        Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial.
        Lancet Diabetes Endocrinol. 2018; 6: 370-381
        • Jabbour S.A.
        • Frias J.P.
        • Hardy E.
        • et al.
        Safety and efficacy of exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy: 52-week results of the DURATION-8 randomized controlled.
        Diabetes Care. 2018; 41: 2136-2146
        • Zinman B.
        • Bhosekar V.
        • Busch R.
        • et al.
        Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial.
        Lancet Diabetes Endocrinol. 2019; 7: 356-367
        • Parker H.E.
        • Habib A.M.
        • Rogers G.J.
        • et al.
        Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells.
        Diabetologia. 2009; 52: 289-298
        • Gorboulev V.
        • Schürmann A.
        • Vallon V.
        • et al.
        Na + -D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion.
        Diabetes. 2012; 61: 187-196
        • Grempler R.
        • Thomas L.
        • Eckhardt M.
        • et al.
        Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors.
        Diabetes Obes Metab. 2012; 14: 83-90
        • Hira T.
        • Koga T.
        • Sasaki K.
        • et al.
        Canagliflozin potentiates GLP-1 secretion and lowers the peak of GIP secretion in rats fed a high-fat high-sucrose diet.
        Biochem Biophys Res Commun. 2017; 492: 161-165
        • Takebayashi K.
        • Hara K.
        • Terasawa T.
        • et al.
        Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial.
        Endocr J. 2017; 64: 923-931
        • Zambrowicz B.
        • Ogbaa I.
        • Frazier K.
        • et al.
        Effects of lx4211, a dual sodium-dependent glucose cotransporters 1 and 2 inhibitor, on postprandial glucose, insulin, glucagon-like peptide 1, and peptide tyrosine in a dose-timing study in healthy subjects.
        Clin Ther. 2013; 35 (1162–73.e8)
        • Powell D.R.
        • Smith M.
        • Greer J.
        • et al.
        LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose.
        J Pharmacol Exp Ther. 2013; 345: 250-259
        • Ahn C.H.
        • Oh T.J.
        • Kwak S.H.
        • et al.
        Sodium-glucose cotransporter-2 inhibition improves incretin sensitivity of pancreatic β -cells in patients with type 2 diabetes.
        Diabetes Obes Metab. 2018; 20: 370-377
        • 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
        • Ferrannini E.
        • Muscelli E.
        • Frascerra S.
        • et al.
        Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients.
        J Clin Invest. 2014; 124: 499-508
        • Martinez R.
        • Al-Jobori H.
        • Ali A.M.
        • et al.
        Endogenous glucose production and hormonal changes in response to canagliflozin and liraglutide combination therapy.
        Diabetes. 2018; 67: 1182-1189
        • Drucker D.J.
        • Nauck M.A.
        The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
        Lancet. 2006; 368: 1696-1705
        • Doumas M.
        • Imprialos Κ.
        • Stavropoulos K.
        • et al.
        Combination of SGLT-2 inhibitors and GLP-1 receptor agonists: potential benefits in surrogate and hard endpoints.
        Curr Pharm Des. 2018; 24: 1879-1886
        • van Baar M.J.B.
        • van Ruiten C.C.
        • Muskiet M.H.A.
        • van Bloemendaal L.
        • IJzerman R.G.
        • van Raalte D.H.
        SGLT2 inhibitors in combination therapy: from mechanisms to clinical considerations in type 2 diabetes management.
        Diabetes Care. 2018; 41: 1543-1556
        • Cho Y.K.
        • Kang Y.M.
        • Lee S.E.
        • et al.
        Efficacy and safety of combination therapy with SGLT2 and DPP4 inhibitors in the treatment of type 2 diabetes: A systematic review and meta-analysis.
        Diabetes Metab. 2018; 44: 393-401
        • Li D.
        • Shi W.
        • Wang T.
        • Tang H.
        SGLT2 inhibitor plus DPP-4 inhibitor as combination therapy for type 2 diabetes: A systematic review and meta-analysis.
        Diabetes Obes Metab. 2018; 20: 1972-1976
        • Seino Y.
        • Yabe D.
        • Sasaki T.
        • et al.
        Sodium-glucose cotransporter-2 inhibitor luseogliflozin added to glucagon-like peptide 1 receptor agonist liraglutide improves glycemic control with bodyweight and fat mass reductions in Japanese patients with type 2 diabetes: A 52-week, open-label, single-arm study.
        J Diabetes Investig. 2018; 9: 332-340
        • Terauchi Y.
        • Utsunomiya K.
        • Yasui A.
        • et al.
        Safety and efficacy of empagliflozin as add-on therapy to GLP-1 receptor agonist (liraglutide) in Japanese patients with type 2 diabetes mellitus: a randomised, double-blind, parallel-group phase 4 study.
        Diabetes Ther. 2019; 10: 951-963
        • Terauchi Y.
        • Fujiwara H.
        • Kurihara Y.
        • et al.
        Long-term safety and efficacy of the sodium-glucose cotransporter 2 inhibitor, tofogliflozin, added on glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: A 52-week open-label, multicenter, post-marketing clinical study.
        J Diabetes Investig. 2019; 10: 1518-1526
        • Pollock C.
        • Stefánsson B.
        • Reyner D.
        • et al.
        Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial.
        Lancet Diabetes Endocrinol. 2019; 7: 429-441
        • Davies M.
        • Pieber T.R.
        • Hartoft-Nielsen M.L.
        • Hansen O.K.H.
        • Jabbour S.
        • Rosenstock J.
        Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial.
        JAMA. 2017; 318: 1460-1470
        • Rosenstock J.
        • Allison D.
        • Birkenfeld A.L.
        • et al.
        Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 randomized clinical trial.
        JAMA. 2019; 321: 1466-1480