ABSTRACT: Abstract Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce glycated hemoglobin (HbA1c), but randomized controlled trial data on their combined use are limited. The LIRA-ADD2SGLT2i trial compared the effect on glycemic control of liraglutide 1.8 mg/day (a GLP-1 analog) vs placebo as add-on to SGLT2i ± metformin in patients with type 2 diabetes (T2D). In this phase 3b trial, patients with T2D on a stable dose of SGLT2i ± metformin and with HbA1c 7.0-9.5% were randomized 2:1 to add either liraglutide 1.8 mg/day or placebo. Exclusion criteria included a history of diabetic ketoacidosis (DKA) while being treated with SGLT2i and/or estimated glomerular filtration rate <60 mL/min/1.73 m2. The primary endpoint was change in HbA1c from baseline at 26 weeks; also assessed after 26 weeks were change in body weight, the proportion of patients achieving HbA1c <7%, and safety. All were analyzed regardless of premature trial product discontinuation or initiation of glucoselowering rescue medication. Overall, 412 patients were screened, 303 were randomized and 280 (92.4%) completed treatment (92.1% with liraglutide, 93.0% with placebo). Baseline characteristics were balanced between treatment groups: mean HbA1c 8.0%, mean body weight 91.1 kg, mean duration of diabetes 9.9 years. At week 26, the mean change in HbA1c from baseline with liraglutide was 0.98% (n=203) vs 0.30% with placebo (n=100) (estimated treatment difference [ETD]: 0.68%, 95% confidence interval [CI]: 0.89, 0.48; p<0.001). The mean change in body weight from baseline with liraglutide was -2.81 kg vs 1.99 kg with placebo (ETD: 0.82 kg; 95% CI: -1.73, 0.09, p=0.077). In the liraglutide group, 51.8% of patients achieved HbA1c <7.0% vs 23.2% in the placebo group (odds ratio: 5.1, 95% CI: 2.67, 9.87; p<0.001). A higher proportion of patients in the liraglutide group reported ?1 treatment-emergent adverse event (AE) than in the placebo group (66.3% vs 47.0%). Nausea was the most frequent AE, occurring in 26.2% of the liraglutide group and 6.0% of the placebo group, and it generally had early onset in the initial 4 weeks and was transient. Similar incidences of hypoglycemic episodes were reported in both groups (8.9% with liraglutide vs 8.0% with placebo); none were severe. The proportion of patients reporting serious AEs was low in both groups (liraglutide 2.5% vs placebo 1.0%). No fatalities occurred in either group and there were no reports of acute renal failure, DKA, diabetic foot ulcers or amputations with liraglutide in combination with SGLT-2i. In patients with T2D, the addition of liraglutide to SGLT2i therapy (± metformin) provided superior glycemic control vs placebo, and had a safety profile consistent with the known safety profile of both drug classes. The LIRA-ADD2SGLT2i is registered with ClinicalTrials.gov NCT02964247.
