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Once-Weekly Semaglutide versus Daily Canagliflozin in Type 2 Diabetes Mellitus (SUSTAIN 8): How Do They Compare?

Authors:
*Ildiko Lingvay,1 Andrei-Mircea Catarig,2 Juan P. Frias,3 Harish Kumar,4 Nanna L. Lausvig,2 Desirée Thielke,2 Carel le Roux,5 Adie Viljoen,6 Rory J. McCrimmon7
Disclosure:

Dr Lingvay reports receiving research grants and consulting fees from Novo Nordisk, and research grants from Gan&Lee, GI Dynamics, Merck, Mylan, Novartis, and Pfizer. She reports receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Mannkind, Sanofi, TARGETPharma Solutions, and Valeritas. Dr Catarig, Dr Lausvig, and Dr Thielke are full-time employees of Novo Nordisk A/S. Dr Frias reports grants and personal fees from Novo Nordisk during the conduct of the study and grants and personal fees from Boehringer Ingelheim, BMS, Eli Lilly, Merck, Pfizer, and Sanofi outside the submitted work. Dr Kumar  reports grants and nonfinancial support from Novo Nordisk during the conduct of the study and outside the submitted work. Dr Roux reports grants and other support from the Health Research Board and the Science Foundation Ireland during the conduct of the study. Outside the submitted work, he reports grants, personal fees, and other support from AnaBio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GI Dynamics, Janssen, Johnson & Johnson, Keyron, Novo Nordisk, and Sanofi. Dr Viljoen reports grants and other support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Napp, Novo Nordisk, and Sanofi, as well as nonfinancial support from Amgen, AstraZeneca, Eli Lilly, Novartis, Novo Nordisk, Regeneron, and Sanofi outside the submitted work. Rory McCrimmon reports personal fees from Eli Lilly, Novo Nordisk, and Sanofi outside the submitted work.

Acknowledgements:

This study was funded by Novo Nordisk. The authors thank Emre Yildirim (Novo Nordisk) for his review and input to this summary, and AXON Communications for medical writing and editorial assistance (funded by Novo Nordisk).

Citation
EMJ Diabet.. ;7[1]:50-52. Abstract No AR03.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

ABSTRACT

Both glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium–glucose cotransporter-2 inhibitors (SGLT-2i) are effective and well-tolerated treatment options approved for the treatment of Type 2 diabetes mellitus (T2DM).1,2 The T2DM guidelines recommended them as second-line therapy after metformin use.3 Head-to-head trials between GLP-1RA and SGLT-2i are scarce, so little information is available to prescribers and patients to guide an informed choice between these two options.  Subcutaneous once-weekly (OW) semaglutide, a GLP-1RA, has demonstrated superior glycaemic control and body weight reductions versus placebo and active comparators across the SUSTAIN clinical trial programme1,4,5  Canagliflozin, an SGLT-2i, also has proven efficacy for glycaemic control and weight loss compared with placebo and active comparators.6–8 Additionally, both OW semaglutide and canagliflozin have shown cardiovascular (CV) benefits in T2DM patients with high CV risk.9,10 The SUSTAIN 8 trial was undertaken as a head-to-head comparison of subcutaneous OW semaglutide with oral once-daily (OD) canagliflozin in patients with T2DM uncontrolled with metformin.

SUSTAIN 8 was a Phase IIIb, randomised, double-blind, double-dummy, active-comparator, parallel-group trial, conducted worldwide across 11 countries. The trial included 788 adults with T2DM and HbA1c 7–10.5%, randomised 1:1 to receive either semaglutide 1.0 mg OW and canagliflozin placebo OD, or canagliflozin 300 mg OD and semaglutide placebo OW for 52 weeks. Primary and confirmatory secondary endpoints included changes from baseline in HbA1c and body weight, respectively. Other efficacy endpoints, along with safety, were also assessed.

The key results from the trial are reported in  Table 1. OW semaglutide was superior to canagliflozin for the primary endpoint of reduction in HbA1c (-1.5%-point versus -1.0%-point). Estimated treatment difference was-0.49%-point (95% confidence interval [CI]: -0.65; -0.33), p<0.0001. Semaglutide also led to superior reductions in body weight versus canagliflozin (-5.3 kg versus -4.2 kg). Estimated treatment difference was -1.06 kg (95% CI: -1.76;-0.36), p=0.0029. Greater proportions of  subjects achieved HbA1c targets (<7.0% and ≤6.5%) and weight-loss responses  (≥5% and ≥10%) with semaglutide versus canagliflozin (p<0.0001 for all [except the difference for weight-loss responses ≥5%;  p=not significant]).

Table 1: Key primary and secondary endpoints in SUSTAIN 8.
CI: confidence interval; ETD: estimated treatment difference; FPG: fasting plasma glucose; HbA1c: haemoglobin A1c; OR: odds ratio; SMBG: self-measured blood glucose.

Overall, 76.0% of subjects treated with semaglutide and 71.8% of subjects treated with canagliflozin experienced adverse events. Consistent with previous SUSTAIN trials, the most frequent adverse events with semaglutide were gastrointestinal (46.9% versus 27.9% with canagliflozin), whereas the most frequent adverse events with canagliflozin were infections and infestations (34.5% versus 29.1% with semaglutide). The rates of premature treatment discontinuation due to adverse events were 9.7% (semaglutide) and 5.1% (canagliflozin), and severe or blood glucose-confirmed symptomatic hypoglycaemia occurred in 1.5% and 1.3% of subjects, respectively.

In summary, the SUSTAIN 8 trial provides clinically relevant information regarding the  head-to-head comparison of a GLP-1RA and SGLT-2i in patients with T2DM. Semaglutide 1.0 mg OW demonstrated superior efficacy compared with canagliflozin 300 mg OD in patients treated with metformin who had uncontrolled T2DM. Both treatments were generally well tolerated, with low rates of hypoglycaemia. Gastrointestinal side effects were more common with semaglutide, while infections were more common with canagliflozin. These study outcomes may be used to guide clinical decision-making when treatment intensification is needed following metformin therapy in T2DM.

References
Novo Nordisk. Ozempic® (semaglutide) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/9728/smpc. Accessed September 2019. Janssen. Invokana® (canagliflozin) Summary of Product Characteristics, 2018. Available at: https://www.medicines.org.uk/emc/product/8855/smpc. Last accessed September 2019. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S90-102. Davies MJ 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;41(12):2669-701. Aroda VR 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):409-18. Cefalu WT et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382(9896):941-50. Lavalle-González FJ et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: A randomised trial. Diabetologia. 2013;56(12):2582-92. Stenlöf K et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-82. Marso SP et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-44. Neal B et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(21):644-57.