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OR22-1 Liraglutide as Add-on to SGLT2 Inhibitors in Patients with Inadequately Controlled Type 2 Diabetes (LIRA-ADD2SGLT2i): A 26-Week, Randomized, Double-Blind, Placebo-Controlled Trial

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.

SUBMITTER: Blonde L

PROVIDER: S-EPMC6554790 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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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.

Project description:Quetiapine extended release (XR) and lithium are treatments with proven efficacy in acute mania. This randomized study evaluated the efficacy and safety of lithium or placebo as add-on to quetiapine XR in adult patients with manic or mixed symptoms of bipolar I disorder. In this 6-week, double-blind study (Trial D144AC00003), adult patients with DSM-IV-TR-diagnosed bipolar I disorder (current episode manic or mixed), a Young Mania Rating Scale (YMRS) total score ?20, and score ?4 on two of four core YMRS items were administered quetiapine XR (400 to 800 mg/day) and randomly assigned to receive add-on lithium (600 to 1,800 mg/day) or placebo. The primary efficacy end point was change in the YMRS total score from baseline to day 43, analyzed using a mixed-model for repeated measures (MMRM) approach. Secondary efficacy and safety end points were also measured. Rating scales were administered by trained staff. Three hundred fifty-six patients treated with quetiapine XR were randomized to add-on lithium (n?=?173) or placebo (n = 183). Two hundred ninety-one patients (81.7%) completed the study. At day 43, least squares mean change in YMRS total score was -22.8 for add-on lithium and -20.1 for add-on placebo, a statistically significant treatment group difference of -2.69 (p < 0.001). On secondary measures, add-on lithium was associated with significant improvements in response, remission, illness severity, and overall illness versus add-on placebo (p < 0.05). The number needed to treat was 9.1 for response and 7.9 for remission for add-on lithium compared with add-on placebo. Lithium in combination with quetiapine XR was generally well tolerated, with a similar profile to quetiapine XR in combination with placebo. The addition of lithium to quetiapine XR therapy was associated with significantly greater efficacy than placebo as add-on and was generally well tolerated in patients with acute bipolar I mania. This study was registered under Clinicaltrials.gov Identifier NCT00931723.

Project description:Abstract In this 56-week, randomized, double-blind, US-based multicenter trial (NCT02963935) we investigated the effects of liraglutide 3.0 mg vs placebo, as adjunct to intensive behavior therapy (IBT) (i.e. reduced calorie intake, increased physical activity [max target: 250 min/week], and 23 counseling sessions). Here we report the effects of treatment on weight change (co-primary endpoints: mean change in body weight [%] and proportion of individuals losing ≥5%), glycemic variables, cardiometabolic risk factors, safety and tolerability. Individuals aged ≥18 years with a body mass index (BMI) ≥30 kg/m2 and without diabetes were randomized 1:1 to liraglutide 3.0 mg or placebo along with IBT. Continuous and categorical variables were calculated using analysis of covariance (ANCOVA) and logistic regression respectively, with treatment, gender and BMI as factors and baseline endpoint as a covariate. Missing values were handled using a jump-to-reference multiple imputation model. There were 282 individuals in the full analysis set; 142 were randomized to liraglutide 3.0 mg (45 y, 16% male, 109 kg, 39 kg/m2) and 140 to placebo (49 y, 17% male, 107 kg, 39 kg/m2); 99% and 93% completed the trial, respectively. The intention to treat analysis demonstrated weight loss at 56 weeks of 7.5% with liraglutide 3.0 mg and 4.0% with placebo (estimated treatment difference (ETD) [95% CI], 3.5% [5.3, 1.6]; p=0.0003). Weight loss in individuals on trial product at 56 weeks was 9.1% (n=114) and 4.8% (n=103), respectively. The proportion of individuals achieving ≥5% weight loss was 61.5% with liraglutide 3.0 mg and 38.8% with placebo (estimated odds ratio (OR) 2.5 [1.5, 4.1], p=0.0003). The proportion who lost >10% was 30.5% and 19.8% (OR 1.8 [1.01, 3.1], p=0.0469), and >15% was 18.1% and 8.9% (OR 2.3 [1.1, 4.7], p=0.0311, respectively. Change in waist circumference was -9.4 cm with liraglutide 3.0 mg vs -6.7 cm with placebo (ETD -2.7 cm [-4.7, -0.8], p=0.006). Significant improvements at 56 weeks were seen for liraglutide 3.0 mg vs placebo in both HbA1c (ETD -0.10% [-0.16, -0.04], p=0.0008) and fasting plasma glucose (ETD ‑0.23 mmol/L [-0.36, -0.11] p=0.0002). Blood pressure (BP) reductions were observed in both treatment arms at 56 weeks, but there were no significant differences between groups in systolic (ETD -2.2 mmHg [‑4.9, 0.5], p=0.11) or diastolic BP (ETD -0.2 mmHg [‑2.2, 1.8], p=0.87), or heart rate (ETD 1.3 bpm [-0.8, 3.4], p=0.23). Lipids were improved vs baseline but no significant differences between treatment arms were observed at 56 weeks (all p>0.05). Liraglutide 3.0 mg was generally well tolerated and no new safety signals were observed in this study. The most frequent adverse events were gastrointestinal (liraglutide 3.0 mg: 71%; placebo: 49%). In conclusion, liraglutide 3.0 mg as an adjunct to IBT resulted in significantly greater weight loss, as compared to IBT and placebo. Supported by Novo Nordisk.

Dataset Information

OR22-1 Liraglutide as Add-on to SGLT2 Inhibitors in Patients with Inadequately Controlled Type 2 Diabetes (LIRA-ADD2SGLT2i): A 26-Week, Randomized, Double-Blind, Placebo-Controlled Trial

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