Semaglutide bests canagliflozin for HbA1c, weight reductions in T2D

In patients with type 2 diabetes (T2D) inadequately controlled on metformin, semaglutide may have a greater impact than canagliflozin in reducing HbA_1c levels and bodyweight, according to the phase IIIb SUSTAIN 8* trial presented at EASD 2019.

“SUSTAIN 8 provides direct evidence of the superiority of semaglutide 1.0 mg over canagliflozin 300 mg in reducing HbA_1c and bodyweight in patients with T2D on metformin therapy, as well as showing similar safety profiles between the two agents,” said Professor Ildiko Lingvay from the UT Southwestern Medical Center in Dallas, Texas, US, and co-authors.

“SUSTAIN 8 [also] provides clinically relevant information regarding the head-to-head comparison of a GLP-1 receptor agonist and SGLT2 inhibitor as second-line therapy in patients with T2D,” said Lingvay.

Participants in this multinational** trial were 788 adults (mean age 56.6 years, 54 percent male, mean baseline weight 90.2 kg) with T2D (HbA_1c 7.0–10.5 percent [mean 8.3 percent]) insufficiently controlled with stable daily metformin. They were randomized 1:1 to receive subcutaneous semaglutide (1.0 mg once/week) or oral canagliflozin (300 mg once/day) plus metformin for 52 weeks.

There was a greater reduction in HbA_1c between baseline and week 52 among semaglutide compared with canagliflozin recipients (estimated treatment difference [ETD], -0.49 percentage points, 95 percent confidence interval [CI], -0.65 to -0.33; p<0.0001). [EASD 2019, oral presentation #52; Lancet Diabetes Endocrinol 2019;doi10.1016/S2213-8587(19)30311-0]

Semaglutide recipients also experienced a greater degree of weight loss during the treatment period than canagliflozin recipients (ETD, -1.06 kg, 95 percent CI, -1.76 to -0.36; p=0.0029).

More semaglutide than canagliflozin recipients experienced weight loss of ≥10 percent (22 percent vs 9 percent; odds ratio [OR], 2.99) and ≥15 percent (6.8 percent vs 0.9 percent; OR, 2.72), a composite of HbA_1c <7 percent, no weight gain, and no severe or blood glucose-confirmed hypoglycaemia (60 percent vs 40 percent; OR, 2.56), and HbA_1c ≤6.5 percent (53 percent vs 24 percent; OR, 4.19; p<0.0001 for all).

Total and LDL-cholesterol and triglyceride levels significantly improved with semaglutide over canagliflozin, while canagliflozin led to greater reductions in blood pressure levels.

Seven percent of patients in each group received rescue medication, most commonly sulphonylurea. Changes in health-related quality of life, as assessed with the SF-36 questionnaire, appeared comparable between groups.

Adverse events (AEs) were reported by 76 and 72 percent of semaglutide and canagliflozin recipients, respectively, and 5 percent of each group reported serious AEs. Gastrointestinal (GI) disorders were the most common AE among semaglutide recipients (47 percent vs 28 percent [canagliflozin]), while infections and infestations were the most common in canagliflozin recipients (35 percent vs 29 percent [semaglutide]). AE-related discontinuations were more common among semaglutide recipients (10 percent vs 5 percent), mainly due to the abovementioned AEs in the respective groups. Severe or blood glucose-confirmed hypoglycaemia occurred infrequently among semaglutide and canagliflozin recipients (2 percent vs 1 percent), while two and four percent, respectively, experienced new or worsening retinopathy.

“These findings support the use of semaglutide as an alternative to canagliflozin in second-line treatment of patients with T2D who need treatment intensification after metformin,” said the researchers. However, they cautioned that patient factors such as cardiovascular disease history need to be taken into account.

“[T]he presence of comorbidities such as heart failure and renal disease should affect the decision of choosing an SGLT2 inhibitor rather than a GLP-1 receptor agonist. Therefore, a personalized approach is recommended, one that is not just based on HbA_1c and bodyweight reductions,” commented Professor André Scheen from Centre Hospitalier Universitaire Liège, Belgium. [Lancet Diabetes Endocrinol 2019:doi:10.1016/S2213-8587(19)30310-9] Cost may also require consideration, he added.

The researchers called for further study into the long-term outcomes of these treatments and acknowledged that the findings may not extend to a real-world, heterogenous T2D population.