Effects of liraglutide compared with placebo on events of acute gallbladder or biliary disease in patients with type 2 diabetes at high risk for cardiovascular events in the LEADER randomized trial

Objective: To explore gallbladder- and biliary tract-related events reported for the liraglutide and placebo groups in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. Research Design and Methods: LEADER was an international, randomized, double-blind, controlled cardiovascular (CV) outcomes trial. Participants with type 2 diabetes at high risk for CV events (n = 9,340) were randomized 1:1 to receive either liraglutide (≤1.8mg daily; n = 4,668) or placebo (n = 4,672), with both groups also receiving standard care (treatment period: 3.5-5 years). Acute gallstone disease was a medical event of special interest. This post hoc analysis categorized captured events of acute gallbladder or biliary disease into four groups: uncomplicated gallbladder stones, complicated gallbladder stones, cholecystitis, and biliary obstruction. Time to first event by treatment group was analyzed using Cox regression. Results: There was an increased risk of acute gallbladder or biliary disease with liraglutide versus placebo (n = 141 of 4,668 vs. n = 88 of 4,672 patients, respectively; hazard ratio [HR] 1.60; 95% CI 1.23, 2.09; P < 0.001). Similar trends were observed for each of the four categories of gallbladder- or biliary tract-related events. Cholecystectomy was performed more frequently in liraglutide-treated patients (HR 1.56; 95% CI 1.10, 2.20; P = 0.013) but for similar proportions of the patients who experienced gallbladder- or biliary tract-related events (57% with liraglutide vs. 59% with placebo). Conclusions: Although LEADER was not specifically designed to assess acute gallbladder or biliary disease, the trial showed an increased risk of gallbladder- or biliary tract-related events with liraglutide versus placebo, which appeared to be consistent across four categories of these events. Further studies should investigate the relevant mechanisms

Liraglutide and Glycaemic Outcomes in the LEADER Trial

Introduction: The LEADER trial was a cardiovascular (CV) outcomes trial in patients with type 2 diabetes at high CV risk that compared liraglutide (n = 4668) with placebo (n = 4672) using a primary composite endpoint of 3-point major adverse CV events. The objective of this post hoc analysis was to investigate glycaemic outcomes across both treatment groups. Methods: Glycated haemoglobin (HbA1c) was measured at randomisation, month 3, month 6 and every 6 months thereafter. Cox regression was used to analyse time to a composite endpoint of glycaemic deterioration, defined as a specified change in HbA1c or a substantial intensification of insulin or oral antihyperglycaemic drug (OAD). The individual components of the composite were also analysed. Results: Baseline characteristics, including insulin and OAD use, were balanced between treatment groups. HbA1c decreased from baseline in both groups, but the reduction was greater with liraglutide [estimated treatment difference at month 36: − 0.40%; 95% confidence interval (CI) − 0.45, − 0.34] despite the addition of more OADs and higher insulin use in the placebo group. Fewer of the patients treated with liraglutide (n = 3202, 68.6%) experienced glycaemic deterioration compared with those administered the placebo (n = 3988, 85.4%; average hazard ratio: 0.50; 95% CI 0.48, 0.53; p &lt; 0.001). Analysis of the individual components showed similar results (both p &lt; 0.001). Conclusions: Type 2 diabetes patients at high risk of CV events who were treated with liraglutide achieved greater reductions in HbA1c, had a lower risk of hypoglycaemia and presented less glycaemic deterioration than similar patients who received the placebo. Nonetheless, progressive loss of glycaemic control occurred in both groups. Trial Registration: ClinicalTrials.gov, NCT01179048. Funding: Novo Nordisk

Myocardial Infarction Subtypes in Patients With Type 2 Diabetes Mellitus and the Effect of Liraglutide Therapy (from the LEADER Trial)

Diabetes mellitus (DM) is a known risk factor for myocardial infarction (MI); however, data regarding MI subtypes in people with diabetes are limited. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (n = 9,340), liraglutide significantly reduced the risk of major adverse cardiovascular (CV) events (composite of CV death, nonfatal MI, or nonfatal stroke) versus placebo in patients with type 2 DM and high CV risk. Liraglutide also reduced risk of first MI (292 events with liraglutide vs 339 with placebo). This post hoc analysis characterized MIs (first and recurrent) occurring in LEADER, by treatment arm and regarding incidence, outcome, subtype, and troponin levels. A total of 780 MIs (first and recurrent) were reported, with fewer in the liraglutide-treatment group than in the placebo-treatment group (359 vs 421, p = 0.022). Numerically fewer MIs were associated with CV death with liraglutide than with placebo (17 vs 28 fatal MIs, p = 0.28). Symptomatic MIs in both arms were mainly non–ST-segment elevation MI (555/641) and spontaneous MI (518/641). Numerically greater proportions of symptomatic MIs were associated with troponin levels ≤5× or ≤10× the upper reference limit with liraglutide versus placebo (p = 0.16 and p = 0.42, respectively). At baseline, more liraglutide-treated patients than placebo-treated patients with MI during the trial had a history of coronary artery bypass graft (p = 0.008), and fewer had peripheral arterial disease in the lower extremities (p = 0.005) and >50% stenosis of the coronary artery, the carotid artery, or other arteries (p = 0.044). In conclusion, this analysis showed that liraglutide reduces the incidence of MIs in patients with type 2 DM at high CV risk and may impact the clinical outcomes of MI

Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke: Post hoc analysis from the leader trial

Background: The glucagon-like peptide-1 analog liraglutide reduced cardiovascular events and mortality in patients with type 2 diabetes mellitus in the LEADER trial (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes). In a post hoc analysis, we evaluated the efficacy of liraglutide in those with and without a history of myocardial infarction (MI) and/or stroke. Methods: LEADER was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk, with a median follow-up of 3.8 years. The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke (major adverse cardiovascular events). Risk groups in this post hoc analysis were defined by history of MI/stroke, established atherosclerotic cardiovascular disease without MI/stroke, or cardiovascular risk factors alone. Results: Of the 9340 patients, 3692 (39.5%) had a history of MI/stroke, 3083 (33.0%) had established atherosclerotic cardiovascular disease without MI/stroke, and 2565 (27.5%) had risk factors alone. Major adverse cardiovascular events occurred in 18.8% of patients with a history of MI/stroke (incidence rate, 5.0 per 100 patient-years), 11.6% of patients with established atherosclerotic cardiovascular disease without MI/stroke (incidence rate, 3.0 per 100 patient-years), and 9.8% of patients with cardiovascular risk factors alone (incidence rate, 2.6 per 100 patient-years). Liraglutide reduced major adverse cardiovascular events in patients with a history of MI/stroke (322 of 1865 [17.3%] versus 372 of 1827 patients [20.4%]; hazard ratio, 0.85; 95% CI, 0.73-0.99) and in those with established atherosclerotic cardiovascular disease without MI/stroke (158 of 1538 [10.3%] versus 199 of 1545 patients [12.9%]; hazard ratio, 0.76; 95% CI, 0.62-0.94) compared with placebo. In patients with risk factors alone, the hazard ratio for liraglutide versus placebo was 1.08 (95% CI, 0.84-1.38, Pinteraction=0.11). Similar results were seen for secondary outcomes across risk groups. Conclusions: In this post hoc analysis of patients with type 2 diabetes mellitus and high cardiovascular risk, liraglutide reduced cardiovascular outcomes both in patients with a history of MI/stroke and in those with established atherosclerotic cardiovascular disease without MI/stroke. The cardiovascular effect appeared neutral in patients with cardiovascular risk factors alone

Long‐term efficacy and safety of combined insulin and GLP‐1 therapy: evidence from the LEADER trial

AIM: Glucagon-like peptide-1 receptor agonist (GLP-1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long-term data are lacking. The aim was to assess the long-term efficacy of the GLP-1RA liraglutide in subgroups by insulin use in the LEADER trial. MATERIALS AND METHODS: LEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal-only insulin, other insulin or no insulin). Insulin was a non-random treatment allocation as part of standard of care therapy. RESULTS: At baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal-only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no-insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal-only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal-only and no-insulin subgroups. CONCLUSIONS: In patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes

Effect of Liraglutide on Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Polyvascular Disease

The presence of polyvascular disease, defined as atherosclerosis involving >1 distinct vascular territory, is a strong, independent predictor of cardiovascular events. In the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), the human glucagon-like peptide 1 analog liraglutide reduced cardiovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. In this post hoc analysis of LEADER, we evaluated the effects of liraglutide stratified by a number of atherosclerotic vascular territories (coronary, cerebrovascular, and peripheral)

Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke.

BACKGROUND: The glucagon-like peptide-1 analog liraglutide reduced cardiovascular events and mortality in patients with type 2 diabetes mellitus in the LEADER trial (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes). In a post hoc analysis, we evaluated the efficacy of liraglutide in those with and without a history of myocardial infarction (MI) and/or stroke. METHODS: LEADER was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk, with a median follow-up of 3.8 years. The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke (major adverse cardiovascular events). Risk groups in this post hoc analysis were defined by history of MI/stroke, established atherosclerotic cardiovascular disease without MI/stroke, or cardiovascular risk factors alone. RESULTS: Of the 9340 patients, 3692 (39.5%) had a history of MI/stroke, 3083 (33.0%) had established atherosclerotic cardiovascular disease without MI/stroke, and 2565 (27.5%) had risk factors alone. Major adverse cardiovascular events occurred in 18.8% of patients with a history of MI/stroke (incidence rate, 5.0 per 100 patient-years), 11.6% of patients with established atherosclerotic cardiovascular disease without MI/stroke (incidence rate, 3.0 per 100 patient-years), and 9.8% of patients with cardiovascular risk factors alone (incidence rate, 2.6 per 100 patient-years). Liraglutide reduced major adverse cardiovascular events in patients with a history of MI/stroke (322 of 1865 [17.3%] versus 372 of 1827 patients [20.4%]; hazard ratio, 0.85; 95% CI, 0.73-0.99) and in those with established atherosclerotic cardiovascular disease without MI/stroke (158 of 1538 [10.3%] versus 199 of 1545 patients [12.9%]; hazard ratio, 0.76; 95% CI, 0.62-0.94) compared with placebo. In patients with risk factors alone, the hazard ratio for liraglutide versus placebo was 1.08 (95% CI, 0.84-1.38, Pinteraction=0.11). Similar results were seen for secondary outcomes across risk groups. CONCLUSIONS: In this post hoc analysis of patients with type 2 diabetes mellitus and high cardiovascular risk, liraglutide reduced cardiovascular outcomes both in patients with a history of MI/stroke and in those with established atherosclerotic cardiovascular disease without MI/stroke. The cardiovascular effect appeared neutral in patients with cardiovascular risk factors alone. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01179048