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Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial.

ABSTRACT: AIM:To compare the effect of liraglutide or placebo added on to sodium-glucose co-transporter-2 inhibitor (SGLT2i)?±?metformin on glycaemic control in patients with type 2 diabetes. MATERIALS AND METHODS:Patients with type 2 diabetes on a stable SGLT2i dose ± metformin (with HbA1c 7.0%-9.5% and body mass index [BMI]???20?kg/m2 ) were randomized 2:1 to add-on liraglutide 1.8?mg/day or placebo in this parallel, double-blind, multinational trial. Primary and confirmatory secondary endpoints were changes in HbA1c and body weight from baseline to week 26, respectively. The proportions of patients achieving HbA1c (<7.0%) targets and safety events after week 26 were also assessed. RESULTS:Of 303 patients randomized (one in error), 280 completed treatment. Mean changes in HbA1c from baseline to week 26 with liraglutide (n = 202) and placebo (n = 100) were?-?0.98% and?-?0.30%, respectively (estimated treatment difference [ETD]: -0.68% [95% CI: -0.89, -0.48]; P?

SUBMITTER: Blonde L

PROVIDER: S-EPMC7317838 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial.

Blonde Lawrence L Belousova Lidia L Fainberg Udi U Garcia-Hernandez Pedro A PA Jain Sunil M SM Kaltoft Margit S MS Mosenzon Ofri O Nafach Jalal J Palle Mads Sundby MS Rea Rosangela R

Diabetes, obesity & metabolism 20200214 6

<h4>Aim</h4>To compare the effect of liraglutide or placebo added on to sodium-glucose co-transporter-2 inhibitor (SGLT2i) ± metformin on glycaemic control in patients with type 2 diabetes.<h4>Materials and methods</h4>Patients with type 2 diabetes on a stable SGLT2i dose ± metformin (with HbA1c 7.0%-9.5% and body mass index [BMI] ≥ 20 kg/m<sup>2</sup> ) were randomized 2:1 to add-on liraglutide 1.8 mg/day or placebo in this parallel, double-blind, multinational trial. Primary and confirmatory s ...[more]

PMID: 31984646

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Project description: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.

Project description:BackgroundManagement of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.MethodsThis was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.ResultsA total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg).ConclusionsDapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone.Trial registrationClinicalTrials.gov: NCT00528879.

Dataset Information

Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial.

Publications

Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial.

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