Abstract
Purpose
To evaluate the efficacy and safety of combination therapy with sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM) or obese adults.
Methods
A meta-analysis was conducted of trials by searching in PubMed, Embase, CENTRAL, Web of Science, and Scopus.
Results
A total of five randomized controlled trials (RCTs) and six nonrandomized controlled trials (NCTs) enrolled 1604 participants were identified for meta-analysis. Compared with control/placebo, the combination therapy group had significantly reduced fasting plasma glucose level and 2 h postprandial glucose by 1.28 mmol/L (95% confidence interval [CI]: −1.39, −1.16; p < 0.001) and 1.34 mmol/L (95% CI: −1.47, −1.21; p < 0.001); glycosylated hemoglobin (HbA1c) by 1.32% (95% CI: −1.43, −1.20; p < 0.001); body weight by 0.93 kg (95% CI: −1.04, −0.83; p < 0.001), and systolic blood pressure (SBP) by 1.05 mmHg (95% CI: −1.17, −0.93; p < 0.001). The incidence of genital mycotic infections and urinary infections did not significantly differ from those in the control group, with relative risks (RRs) of 1.67 (95% CI: 0.85, 3.27; p = 0.651) and 1.25 (95% CI: 0.73, 2.15; p = 0.905), respectively. A decreased incidence of cardiovascular events was seen in the combination therapy group (RR = 0.19; 95% CI: 0.04, 0.96; p = 0.403), while an incidence of hypoglycemia was reported (RR = 2.22; 95% CI: 1.20, 4.10; p = 0.71).
Conclusions
SGLT2 inhibitors and GLP-1 agonists combination treatment improved glycemic control, reduced body weight, and decreased SBP without an increase in total adverse events or genital and urinary infections in patients with T2DM or obesity.
Similar content being viewed by others
References
E.C. Chao, R.R. Henry, SGLT2 inhibition-a novel strategy for diabetes treatment. Nat. Rev. Drug Discov. 9, 551–559 (2010)
M.A. Nauck, G. Kemmeries, J.J. Holst et al. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 60, 1561–1565 (2011)
A.A. Tahrani, A.H. Barnett, C.J. Bailey, Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 12, 566–592 (2016)
L.L. Baggio, D.J. Drucker, Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007)
J.P.H. Wilding, S.P. Rajeev, R.A. DeFronzo, Positioning SGLT2 inhibitors/ incretin-based therapies in the treatment algorithm. Diabetes Care 39(2), S154–S164 (2016)
J. Liu, L. Li, K. Deng et al. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ 357, j2499 (2017)
M. Monami, C. Nardini, E. Mannucci, Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes. Metab. 16(5), 457–466 (2014)
RobertS. Busch, MichaelP. Kane, Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes. Postgrad. Med. 129, 686–697 (2017)
B. Hutton, G. Salanti, D.M. Caldwell et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann. Intern. Med. 162, 777–784 (2015)
Cochrane handbook for systematic reviews of interventions. https://training.cochrane.org/handbook
J.P. Frías, C. Guja, E. Hardy et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 4, 1004–1016 (2016)
S.A. Jabbour, J.P. Frias, E. Hardy, A. Ahmed, H. Wang, P. Ohman 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 trial. Diabetes Care 41(10), 2136–2146 (2018)
P. Lundkvist, C.D. Sjöström, S. Amini et al. Dapagliflozin once-daily and exenatide once-weekly dual therapy: a 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes Obes. Metab. 19, 49–60 (2017)
P. Lundkvist, M.J. Pereira, P. Katsogiannos et al. Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: sustained reductions in body weight, glycaemia and blood pressure over 1 year. Diabetes Obes. Metab. 19, 1276–1288 (2017)
B. Ludvik, J.P. Frías, F.J. Tinahones 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. 6, 370–381 (2018)
R.M. Saroka, M.P. Kane, R.S. Busch et al. SGLT-2 inhibitor therapy added to GLP-1 agonist therapy in the management of T2DM. Endocr. Pract. 21, 1315–1322 (2015)
G. Fulcher, D.R. Matthews, V. Perkovic et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes. Metab. 18, 82–91 (2016)
H. Deol, L. Lekkakou, A.K. Viswanath, Combination therapy with GLP-1 analogues and SGLT-2 inhibitors in the management of diabesity: the real world experience. Endocrine 55, 173–178 (2017)
Y. Terauchi, K. Utsunomiya, A. Yasui,, 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. 10(3), 951–963 (2019)
S.I. Harashima, N. Inagaki, K. Kondo et al. Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: a 52-week, open-label, phase IV study. Diabetes Obes. Metab. 20, 1770–1775 (2018)
H. Ishihara, S. Yamaguchi, I. Nakao, T. Sakatani, Ipragliflozin add-on therapy to a GLP-1 receptor agonist in Japanese patients with type 2 diabetes (AGATE): a 52-week open-label study. Diabetes Ther. 9(4), 1549–1567 (2018)
B. Neal, V. Perkovic, K.W. Mahaffey et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377, 644–657 (2017)
S.L. Zheng, A.J. Roddick, R. Aghar-Jaffar et al. Association between use of sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA 319, 1580–1591 (2018)
S.H. Min, J.H. Yoon, S.J. Moon et al. Combination of sodium–glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor in type 2 diabetes: a systematic review with meta-analysis. Sci. Rep. 8, 4466 (2018)
H. Tang, W. Cui, D. Li et al. Sodium-glucose co-transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Diabetes Obes. Metab. 19, 142–147 (2017)
Y. Yang, S. Chen, H. Pan et al. Safety and efficiency of SGLT2 inhibitor combining with insulin in subjects with diabetes: Systematic review and meta-analysis of randomized controlled trials. Medicine 96, e6944 (2017)
A.A. Tahrani, A.H. Barnett, C.J. Bailey, Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 12, 566–592 (2016)
I.J. Neeland, D.K. McGuire, R. Chilton et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diabetes Vasc. Dis. Res. 13, 119–126 (2016)
S.P. Marso, G.H. Daniels, K. Brown-Frandsen et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016)
C. Sorli, S.-I. Harashima, G.M. Tsoukas 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. 5, 251–260 (2017)
R.R. Holman, M.A. Bethel, R.J. Mentz et al. Effects of onceweekly exenatide on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 377, 1228–1239 (2017)
E. Goncalves, D.S.H. Bell, Combination treatment of SGLT2 inhibitors and GLP-1 receptor agonists: symbiotic effects on metabolism and cardiorenal risk. Diabetes Ther. 9, 919–926 (2018)
M. Guo, J. Ding, J. Li et al. SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes. Metab. 20, 1977–1982 (2018)
Author contributions
M.G. and Y.X. participated in the study conception and design. M.G. and J.G. acquired reports of trials and extracted data. M.G., F.T., and X.M. performed data analyses. J.C., Q.C., and Y.P. checked for statistical consistency. M.G., J.G., and F.T. contributed to data interpretation and drafted the paper. Y.X., Y.L., and Z.J. critically reviewed the paper. M.G., J.G., and Y.X. contributed to the discussion, were guarantors of this work, had full access to all data in the study, and took responsibility for the integrity and accuracy of the data analysis. All authors approved the final version of this paper.
Funding
This study was funded by grants from the National Natural Science Foundation of Chian (grant number 81800741) and Luzhou-Southwest Medical University cooperation project (grant number 2016LZXNYD-G02).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors gratefully acknowledge BioMed Proofreading for English expression polished and declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Guo, M., Gu, J., Teng, F. et al. The efficacy and safety of combinations of SGLT2 inhibitors and GLP-1 receptor agonists in the treatment of type 2 diabetes or obese adults: a systematic review and meta-analysis. Endocrine 67, 294–304 (2020). https://doi.org/10.1007/s12020-019-02175-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-019-02175-6