BARCELONA – The glucagonlike peptide–1 receptor antagonist semaglutide (Ozempic) produced greater reductions in glycated hemoglobin and body weight than the sodium-glucose cotransporter 2 inhibitor canagliflozin (Invokana) in second-line treatment in patients with type 2 diabetes after metformin and lifestyle modifications, researchers reported at the annual meeting of the European Association for the Study of Diabetes.
Dr. Ildiko Lingvay
The year-long SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) 8 trial comparing semaglutide and canagliflozin is one of the few head-to-head comparisons of the glucagonlike peptide–1 receptor antagonist (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitor classes of drugs.
Findings showed overall changes in HbA1c level from baseline to week 52 of –1.5 percentage points with semaglutide and –1.0 percentage point with canagliflozin, and changes in body weight during the same time of –5.3 kg and –4.2 kg, respectively. The estimated treatment differences were –0.49 percentage points for HbA1c (P less than .001) and –1.06 kg for body weight (P less than .0029).
A significantly higher percentage of patients receiving semaglutide also achieved HbA1c targets at 52 weeks, compared with those receiving canagliflozin: 66.1% versus 45.1%, respectively, achieved the American Diabetes Association’s target of less than 7%, and 52.8% versus 23.6% (P less than .0001) reached the lower target of 6.5% or lower, as set by the American Association of Clinical Endocrinologists.
Furthermore, a significantly higher proportion of patients in the semaglutide arm achieved 10% or more weight loss by the end of the study (22.3% vs. 8.9% in the canagliflozin arm; P less than .0001), with a trend for 5% or greater weight loss favoring semaglutide (51.1% vs. 46.6%, P = .21). A post hoc analysis also showed that patients treated with semaglutide could achieve a weight loss of 15% or more (6.8% vs. 0.9% for canagliflozin, P = .0001).
“SUSTAIN 8 provides clinically relevant information regarding the head-to-head comparison of these two very commonly used glucose-lowering classes [of drugs] as second-line therapy in patients with type 2 diabetes,” lead study author Ildiko Lingvay, MD, said. The findings support the use of semaglutide as an alternative to canagliflozin when treatment intensification after metformin is needed, Dr. Lingvay and coauthors concluded in an article published simultaneously in Lancet Diabetes & Endocrinology (2019 Sep 17. doi: 10.1016/S2213-8587[19]30311-0).
Dr. Lingvay of the University of Texas in Dallas observed that both GLP-1 RAs and SGLT2 inhibitors are recommended as second-line treatment after metformin and lifestyle modifications, particularly when there is a need to minimize the risk for hypoglycemia and weight gain, and there is established cardiovascular disease. Despite their wide endorsement, however, there has really been only one other head-to-head trial that evaluated the two drug classes – the PIONEER 2 study, which compared oral semaglutide and the SGLT2 inhibitor empagliflozin (Jardiance). Another trial, DURATION-8, compared the GLP-1 RA exenatide (Byetta) or the SGLT2 inhibitor dapagliflozin (Farxiga) with an exenatide-dapagliflozin combination, but it did not directly compare the two drug classes.
SUSTAIN 8 was a phase 3b, randomized, double-blind, parallel-group, controlled trial that compared once-weekly subcutaneous semaglutide 1.0 mg and daily oral canagliflozin 300 mg as add-on treatments to metformin in 788 individuals with type 2 diabetes. Participants had to have a starting HbA1c of between 7.0% and 10.0%, to be on a stable dose of metformin, and to have an estimated glomerular filtration rate of 60 mL/min per 1.73 m3 or higher.
Of the 394 patients randomized to semaglutide, 83.3% completed the study treatment and 15.7% discontinued prematurely, most often because of adverse events (9.7%). Of the remaining 394 patients randomized to canagliflozin therapy, 87.1% completed treatment and 12.9% discontinued prematurely, again mostly for adverse events (5.1%).
Overall the rate of any adverse events (76.0% vs. 71.8%) or serious adverse events (4.6% vs. 5.3%) were similar between the semaglutide and canagliflozin groups. As expected, more gastrointestinal side effects were seen in patients treated with semaglutide than in those treated with canagliflozin (46.9% vs. 27.9%), and there were more infections in the canagliflozin group (29.1% vs. 34.5%). Hypoglycemic episodes were “very rare in this population,” Dr. Lingvay reported. Rates of severe or confirmed hypoglycemia were 1.5% and 1.3% for the respective arms.
Other findings of note were improved fasting blood lipids – with greater changes in total serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides seen with semaglutide than canagliflozin. Systolic blood pressure dropped in both groups, with a greater change in the canagliflozin than semaglutide group (–5.5 mm Hg vs. –3.5 mm Hg; P = .0452).