The Lancets, Diabetes and Endocrinology has just published the results of SUSTAIN 8 clinical trial. The study compared the efficacy and safety of semaglutide 1.0 mg/week versus canagliflozin 300 mg/day in patients with uncontrolled diabetes taking only metformin.
Investigators recruited and followed a group of 800 adults with baseline A1c 7.0-10.5% from 111 centers in 11 countries. They found that the addition of semaglutide to metformin lowered A1c and body weight more than canagliflozin by 0.5% and 2.2 lbs respectively. The trial observed that patients receiving semaglutide experienced higher rates of nausea, while those taking canagliflozin developed more urinary tract infections.
Current ADA and AACE guidelines recommend the use of a GLP-1 agonist or SGLT-2 inhibitor after metformin in uncontrolled type 2 diabetes. Although the study did not compare GLP-1 agonists and SGLT-2 inhibitors as a class, it did suggest initiation of semaglutide 1.0 mg/week over SGLT-2 inhibitors. SGLT-2 inhibitors are regarded to be clinically similar.
An SGLT-2 inhibitor, however, would be a better second-line agent after metformin in diabetes patients with clinical or subclinical heart failure but with proper kidney function (eGFR >45). I anticipate that ADA and AACE guidelines will incorporate SUSTAIN 8 results in their next published standards.
The Lancet, Diabetes and Endocrinology
Existing guidelines for management of type 2 diabetes recommend a patient-centered approach to guide the choice of pharmacological agents. Although glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT2) inhibitors are increasingly used as second-line agents, direct comparisons between these treatments are insufficient. In the SUSTAIN 8 trial, we compared the efficacy and safety of semaglutide (a GLP-1 receptor agonist) with canagliflozin (an SGLT2 inhibitor) in patients with type 2 diabetes.
This was a double-blind, parallel-group, phase 3b, randomized controlled trial done at 111 centers in 11 countries.
Eligible patients were at least 18 years old and had uncontrolled type 2 diabetes (A1c 7.0–10.5%) on stable daily metformin therapy.
Patients were randomly assigned (1:1) by use of an interactive web response system to subcutaneous semaglutide 1.0 mg once weekly or oral canagliflozin 300 mg once daily.
- Primary endpoint was change from baseline in A1c.
- Confirmatory secondary endpoint was change from baseline in bodyweight, both at week 52.
The primary analysis population included all randomly assigned patients, using on-treatment data collected before initiation of rescue medication.
The safety analysis was done on a population that included all patients exposed to at least one dose of trial product. The trial was powered for A1c and bodyweight superiority under reasonable assumptions.
Between March 15, 2017, and Nov 16, 2018, 788 patients were randomly assigned to semaglutide 1.0 mg (394 patients) or canagliflozin 300 mg (394 patients).
739 patients completed the trial (367 in the semaglutide group and 372 in the canagliflozin group).
From overall baseline mean, patients receiving semaglutide had significantly greater reductions in A1c and bodyweight than those receiving canagliflozin (A1c estimated treatment difference [ETD] −0.49 percentage points, p<0.0001; and bodyweight ETD −1.06 kg, p=0.0029).
Gastrointestinal disorders, most commonly nausea, were the most frequently reported adverse events with semaglutide, occurring in 184 (47%) of 392 patients; whereas infections and infestations (defined using the Medical Dictionary for Regulatory Activities, version 21.0), most commonly urinary tract infections, occurred more frequently with canagliflozin, in 136 (35%) of 394 patients.
Premature treatment discontinuation because of adverse events occurred in 38 (10%) of 392 patients with semaglutide and in 20 (5%) of 394 patients with canagliflozin. One fatal adverse event confirmed unlikely to be caused by treatment occurred in the semaglutide group.
Once-weekly semaglutide 1.0 mg was superior to daily canagliflozin 300 mg in reducing A1c and bodyweight in patients with type 2 diabetes uncontrolled on metformin therapy. These outcomes might guide treatment intensification choices.