Dataset Information

Effects of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials.

ABSTRACT: Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (<25, ?25-<30, ?30-<35 and ?35?kg/m² ), and CV and kidney outcomes with GLP-1 RA versus placebo were analysed. All baseline BMI data from LEADER (n = 9331) and SUSTAIN 6 (n = 3290) were included (91% and 92% of patients with overweight or obesity, respectively). In SUSTAIN 6, nominally significant heterogeneity of semaglutide efficacy by baseline BMI was observed for CV death/myocardial infarction/stroke (major adverse CV events, primary outcome of both; P_interaction =?.02); otherwise, there was no statistical heterogeneity for either GLP-1 RA versus placebo across BMI categories for key CV and kidney outcomes. The lack of statistical heterogeneity from these cardiorenal outcomes implies that liraglutide and semaglutide may be beneficial for many patients and is probable not to depend on their baseline BMI, but further study is needed.

SUBMITTER: Verma S

PROVIDER: S-EPMC7754406 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effects of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials.

Verma Subodh S McGuire Darren K DK Bain Stephen C SC Bhatt Deepak L DL Leiter Lawrence A LA Mazer C David CD Monk Fries Tea T Pratley Richard E RE Rasmussen Søren S Vrazic Hrvoje H Zinman Bernard B Buse John B JB

Diabetes, obesity & metabolism 20200904 12

Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. The ...[more]

PMID: 32744418

Similar Datasets

Project description:BackgroundWe assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes.MethodsPooled (n=12 637) and by-trial data from SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; n=3297) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; n=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persistent eGFR reduction (30%, 40%, 50%, and 57%) from baseline.ResultsThe median follow-up durations were 2.1 years for SUSTAIN 6 and 3.8 years for LEADER. In the pooled analysis, semaglutide/liraglutide lowered albuminuria from baseline to 2 years after randomization by 24% versus placebo (95% CI, 20%-27%; P<0.001). Significant reductions were also observed in by-trial data analyses (P<0.001 for all), the largest being with semaglutide 1.0 mg (33% [95% CI, 24%-40%]; P<0.001) at 2 years. With semaglutide 1.0 mg and liraglutide, eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m2/y (P<0.0001 and P<0.001), respectively, versus placebo. Effects appeared larger in patients with baseline eGFR <60 versus ≥60 mL/min/1.73 m2 (Pinteraction=0.06 and 0.008 for semaglutide 1.0 mg and liraglutide, respectively). Semaglutide/liraglutide significantly lowered risk of persistent 40% and 50% eGFR reductions versus placebo (hazard ratio [HR], 0.86 [95% CI, 0.75-0.99]; P=0.039 and HR, 0.80 [95% CI, 0.66-0.97]; P=0.023, respectively). Similar, nonsignificant, directional results were observed for 30% and 57% eGFR reductions (HR, 0.92 [95% CI, 0.84-1.02]; P=0.10 and HR, 0.89 [95% CI, 0.69-1.13]; P=0.34). In patients with baseline eGFR 30 to <60 mL/min/1.73 m2, the likelihood of persistent reduction for all thresholds was increased, ranging from HR 0.71 for 30% reduction (95% CI, 0.59-0.85; P=0.0003, Pinteraction=0.017) to 0.54 for 57% reduction (95% CI, 0.36-0.81; P=0.003, Pinteraction=0.035).ConclusionsIn patients with type 2 diabetes, semaglutide/liraglutide offered kidney-protective effects, which appeared more pronounced in patients with preexisting chronic kidney disease.

Project description:The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.

Project description:AIM:To investigate treatment satisfaction with semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, versus placebo/active comparators in the SUSTAIN clinical trial programme. METHODS:In SUSTAIN 2-5 and 7, the Diabetes Treatment Satisfaction Questionnaire was used to evaluate patient-perceived treatment satisfaction, hyperglycaemia and hypoglycaemia. Post hoc subgroup analyses were conducted to explore the effects of gastrointestinal adverse events (GI AEs), weight loss (?5%) or achieving glycaemic (HbA1c?< 7%) targets on treatment satisfaction. RESULTS:Overall treatment satisfaction increased from baseline to end of treatment with all treatments across trials. Improvements were significantly greater with semaglutide versus comparators/placebo in SUSTAIN 2-5 (all P < 0.05), and generally greater in patients who achieved versus did not achieve weight loss and glycaemic targets, often with greater improvements with semaglutide 1.0 mg versus comparator/placebo in both weight loss groups. In SUSTAIN 7, improvements in overall treatment satisfaction were generally similar between semaglutide and dulaglutide, irrespective of weight loss or glycaemic control. In SUSTAIN 7, changes in overall treatment satisfaction score were generally lower in patients with versus without GI AEs at week 16 (except dulaglutide 0.75?mg), but similar by week 40. Perceived hyperglycaemia was significantly reduced from baseline to end of treatment with semaglutide versus all comparators/placebo (all P?<?0.05). No differences between treatments were observed for perceived hypoglycaemia. CONCLUSIONS:Semaglutide was associated with significantly greater (SUSTAIN 2-5) or similar (SUSTAIN 7) improvements in overall treatment satisfaction versus comparators/placebo. Improvements in overall treatment satisfaction were generally greater in patients achieving versus not achieving treatment targets. Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4), NCT02305381 (SUSTAIN 5) and NCT02648204 (SUSTAIN 7). EudraCT: 2012-004827-19 (SUSTAIN 2), 2012-004826-92 (SUSTAIN 3), 2013-004392-12 (SUSTAIN 4), 2013-004502-26 (SUSTAIN 5) and 2014-005375-91 (SUSTAIN 7).

Dataset Information

Effects of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials.

Publications

Effects of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets