scholarly journals The effect of liraglutide and sitagliptin on oxidative stress in persons with type 2 diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Suvanjaa Sivalingam ◽  
Emil List Larsen ◽  
Daniel H. van Raalte ◽  
Marcel H. A. Muskiet ◽  
Mark M. Smits ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Nucleic Acid ◽  
Urinary Excretion ◽  
Post Hoc Analysis ◽  
Significant Difference ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Post Hoc

AbstractGlucagon-like peptide 1 receptor agonists have shown cardioprotective effects which have been suggested to be mediated through inhibition of oxidative stress. We investigated the effect of treatment with a glucagon-like peptide 1 receptor agonist (liraglutide) on oxidative stress measured as urinary nucleic acid oxidation in persons with type 2 diabetes. Post-hoc analysis of two independent, randomised, placebo-controlled and double-blinded clinical trials. In a cross-over study where persons with type 2 diabetes and microalbuminuria (LIRALBU, n = 32) received liraglutide (1.8 mg/day) or placebo for 12 weeks in random order, separated by 4 weeks of wash-out. In a parallel-grouped study where obese persons with type 2 diabetes (SAFEGUARD, n = 56) received liraglutide (1.8 mg/day), sitagliptin (100 mg/day) or placebo for 12 weeks. Endpoints were changes in the urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG)) and RNA oxidation [8-oxo-7,8-dihydroguanosine (8-oxoGuo)]. In LIRALBU, we observed no significant differences between treatment periods in urinary excretion of 8-oxodG [0.028 (standard error (SE): 0.17] nmol/mmol creatinine, p = 0.87) or of 8-oxoGuo [0.12 (0.12) nmol/mmol creatinine, p = 0.31]. In SAFEGUARD, excretion of 8-oxodG was not changed in the liraglutide group [2.8 (− 8.51; 15.49) %, p = 0.62] but a significant decline was demonstrated in the placebo group [12.6 (− 21.3; 3.1) %, p = 0.02], resulting in a relative increase in the liraglutide group compared to placebo (0.16 nmol/mmol creatinine, SE 0.07, p = 0.02). Treatment with sitagliptin compared to placebo demonstrated no significant difference (0.07 (0.07) nmol/mmol creatinine, p = 0.34). Nor were any significant differences for urinary excretion of 8-oxoGuo liraglutide vs placebo [0.09 (SE: 0.07) nmol/mmol creatinine, p = 0.19] or sitagliptin vs placebo [0.07 (SE: 0.07) nmol/mmol creatinine, p = 0.35] observed. This post-hoc analysis could not demonstrate a beneficial effect of 12 weeks of treatment with liraglutide or sitagliptin on oxidatively generated modifications of nucleic acid in persons with type 2 diabetes.

scholarly journals Efficacy and Safety of Semaglutide for Type 2 Diabetes by Race and Ethnicity: A Post Hoc Analysis of the SUSTAIN Trials

2019 ◽  
Vol 105 (2) ◽  
pp. 543-556 ◽  
Author(s):  
Cyrus DeSouza ◽  
Bertrand Cariou ◽  
Satish Garg ◽  
Nanna Lausvig ◽  
Andrea Navarria ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Race And Ethnicity ◽  
Efficacy And Safety ◽  
Post Hoc Analysis ◽  
Percentage Points ◽  
Treatment Responses ◽  
Glucagon Like Peptide 1 ◽  
Post Hoc

Abstract Context Variations in the prevalence and etiology of type 2 diabetes (T2D) across race and ethnicity may affect treatment responses. Semaglutide is a glucagon-like peptide-1 analog approved for once-weekly, subcutaneous treatment of T2D. Objective To compare semaglutide efficacy and safety in race and ethnicity subgroups across the SUSTAIN trials. Design Post hoc analysis of data from phase 3 randomized SUSTAIN 1–5 and 7 (pooled), and SUSTAIN 6 trials. Participants 3074 subjects (SUSTAIN 1–5 and 7) and 1648 subjects (SUSTAIN 6). Interventions Semaglutide 0.5 or 1.0 mg, placebo, or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg, insulin glargine 100IU/ml and dulaglutide 0.75 or 1.5 mg). Main Outcome Measures Change in hemoglobin A1C (HbA1c) and body weight from baseline to weeks 30, 40 and 104, and other efficacy and safety endpoints. Results HbA1c was reduced from baseline by 1.0 to 1.5 percentage points and 1.3 to 2.0 percentage points, and body weight was reduced by 2.3 to 4.7 kg and 3.6 to 6.1 kg with semaglutide 0.5 and 1.0 mg, respectively, across race and ethnicity subgroups. Minor changes in blood pressure and lipid profiles were observed. Adverse events (AEs) were reported in similar proportions of subjects across trials. More Asian versus other race subgroups discontinued treatment prematurely due to AEs. The most commonly reported AEs were gastrointestinal disorders. Conclusions In this SUSTAIN trials post hoc analysis, semaglutide was associated with consistent and clinically relevant reductions in HbA1c and body weight in subjects with T2D, with minor variations in efficacy and safety outcomes associated with race or ethnicity.

Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes

2013 ◽  
Vol 305 (3) ◽  
pp. H295-H304 ◽  
Author(s):  
Akio Monji ◽  
Toko Mitsui ◽  
Yasuko K. Bando ◽  
Morihiko Aoyama ◽  
Toshimasa Shigeta ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Receptor Activation ◽  
Left Ventricular ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
And Oxidative Stress

Glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is a remedy for type 2 diabetes mellitus (T2DM). Ex-4 ameliorates cardiac dysfunction induced by myocardial infarction in preclinical and clinical settings. However, it remains unclear whether Ex-4 may modulate diabetic cardiomyopathy. We tested the impact of Ex-4 on two types of diabetic cardiomyopathy models, genetic (KK) and acquired T2DM induced by high-fat diet [diet-induced obesity (DIO)], to clarify whether Ex-4 may combat independently of etiology. Each type of mice was divided into Ex-4 (24 nmol·kg−1·day−1 for 40 days; KK-ex4 and DIO-ex4) and vehicle (KK-v and DIO-v) groups. Ex-4 ameliorated systemic and cardiac insulin resistance and dyslipidemia in both T2DM models. T2DM mice exhibited systolic (DIO-v) and diastolic (DIO-v and KK-v) left ventricular dysfunctions, which were restored by Ex-4 with reduction in left ventricular hypertrophy. DIO-v and KK-v exhibited increased myocardial fibrosis and steatosis (lipid accumulation), in which were observed cardiac mitochondrial remodeling and enhanced mitochondrial oxidative damage. Ex-4 treatment reversed these cardiac remodeling and oxidative stress. Cytokine array revealed that Ex-4-sensitive inflammatory cytokines were ICAM-1 and macrophage colony-stimulating factor. Ex-4 ameliorated myocardial oxidative stress via suppression of NADPH oxidase 4 with concomitant elevation of antioxidants (SOD-1 and glutathione peroxidase). In conclusion, GLP-1R agonism reverses cardiac remodeling and dysfunction observed in T2DM via normalizing imbalance of lipid metabolism and related inflammation/oxidative stress.

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: A systematic review and meta-analysis

2020 ◽  
Vol 27 (18) ◽  
pp. 1922-1930 ◽  
Author(s):  
Vishnu Priya Pulipati ◽  
Venkatesh Ravi ◽  
Priyanjali Pulipati
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Meta Analysis ◽  
Composite Endpoint ◽  
Primary Composite Endpoint ◽  
Significant Difference ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background Glucagon-like peptide-1 receptor agonists (GLP1RAs) are relatively newer anti-hyperglycemic agents, which have demonstrated cardiovascular benefits in patients with type 2 diabetes mellitus. Design We performed a meta-analysis of randomized controlled trials to evaluate the cardiovascular outcomes of GLP1RAs compared to placebo in type 2 diabetes mellitus patients. We performed an additional subgroup analysis to evaluate the role of GLP1RAs in patients with chronic kidney disease. Methods MEDLINE, Cochrane and ClinicalTrials.gov databases were searched from inception to 15 July 2019. The authors extracted relevant information from articles and independently assessed the study quality. Results Compared to placebo, GLP1RAs demonstrated a significant reduction in all-cause mortality (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.82–0.95; P < 0.001), cardiovascular mortality (OR 0.88, 95% CI 0.81–0.96; P = 0.004), primary composite endpoint (OR 0.86, 95% CI 0.80–0.91; P < 0.001) and non-fatal stroke (OR 0.86, 95% 0.77–0.95; P = 0.004). There was no statistical difference in non-fatal myocardial infarction (OR 0.92, 95% CI 0.83–1.01; P = 0.09). In subgroup analyses of patients with estimated glomerular filtration rate less than 60 ml/min/1.73 m2 and less than 30 ml/min/1.73 m2, there was no significant difference in the primary composite endpoint. Conclusions GLP1RAs demonstrated a significant reduction in all-cause mortality, cardiovascular mortality, primary composite endpoint and non-fatal stroke in patients with type 2 diabetes mellitus. There was no significant difference in the primary composite endpoint in patients with type 2 diabetes mellitus and chronic kidney disease.

scholarly journals Reductions in Insulin Resistance are Mediated Primarily via Weight Loss in Subjects With Type 2 Diabetes on Semaglutide

2019 ◽  
Vol 104 (9) ◽  
pp. 4078-4086 ◽  
Author(s):  
Vivian A Fonseca ◽  
Matthew S Capehorn ◽  
Satish K Garg ◽  
Esteban Jódar Gimeno ◽  
Oluf H Hansen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Weight Loss ◽  
Extended Release ◽  
Outcome Measure ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Post Hoc ◽  
The Relationship

AbstractContextSemaglutide, a once-weekly glucagon-like peptide-1 analog approved for use in patients with type 2 diabetes (T2D), demonstrated superior body weight (BW) reductions and decreased insulin resistance (IR) vs comparators across the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) 1–3 clinical trials.ObjectiveTo investigate the relationship between IR and BW across the SUSTAIN 1–3 trials.DesignPost hoc analysis of the SUSTAIN 1–3 trials.SettingThree hundred and eleven sites in 30 countries.Patients or other participants2432 subjects with T2D.InterventionsSemaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg).Main Outcome MeasureTo assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW.ResultsAcross SUSTAIN 1–3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7 kg to 4.3 kg; P < 0.0001) and semaglutide 1.0 mg (4.5 kg to 6.1 kg; P < 0.0001) vs comparators (1.0 kg to 1.9 kg). There were greater reductions in IR with semaglutide 0.5 mg (27% to 36%) and semaglutide 1.0 mg (32% to 46%) vs comparators (17% to 28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70% to 80% and 34% to 94%, for semaglutide 0.5 mg and 1.0 mg, respectively, vs comparator).ConclusionsSemaglutide consistently reduced BW and IR in subjects with T2D in SUSTAIN 1–3. In this analysis, IR improvement was positively associated with, and primarily mediated by, the effect of semaglutide on BW.

Abstract 13814: Semaglutide Reduces Mace Consistently Across Baseline Triglyceride Levels in Patients With Type 2 Diabetes: A Post Hoc Analysis of the Sustain 6 and Pioneer 6 Trials

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Subodh Verma ◽  
Lawrence A Leiter ◽  
Marie M Michelsen ◽  
David Orsted ◽  
Soren Rasmussen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cox Regression ◽  
Density Lipoprotein ◽  
Statin Treatment ◽  
Continuous Variable ◽  
Post Hoc Analysis ◽  
Glucagon Like Peptide 1 ◽  
Post Hoc ◽  
The Impact

Introduction: Elevated triglyceride (TG) levels may predict CV events, although this has not been evaluated in large contemporary trials. The effects of glucagon-like peptide-1 receptor agonists on major adverse CV events (MACE) across TG levels are not fully characterized. SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) were randomized, CV outcomes trials investigating once-weekly and oral semaglutide vs placebo, respectively, in patients with type 2 diabetes at high CV risk. We performed a post hoc analysis to assess the effect of semaglutide vs placebo on the primary endpoints, MACE (CV death, nonfatal myocardial infarction, or nonfatal stroke), and its components in these two trials pooled, across baseline TG levels. Methods: The risk of first MACE with semaglutide vs placebo was evaluated across three baseline TG groups (≤151, >151-≤205, and >205 mg/dL). The effect of semaglutide vs placebo on MACE was estimated with Cox regression by TG level categorically, and continuously when adjusting for baseline TG and high-density lipoprotein-cholesterol (HDL-C) levels. The impact of statin treatment was also assessed. Results: In total, 6,417 patients had baseline TG measurements: 3,191 (49.7%) ≤151, 1,459 (22.7%) >151-≤205, and 1,767 (27.5%) >205 mg/dL; mean (±SD) TGs were 107.3 (26.0), 176.6 (15.6), and 326.5 (197.1) mg/dL, respectively. Overall, semaglutide reduced TGs vs placebo by 5% in SUSTAIN 6 and 6% in PIONEER 6 (p<0.01). The incidence of MACE with placebo increased across increasing TG levels (Figure) . Semaglutide generally reduced the risk of MACE and its components vs placebo across TG groups. Results were consistent when evaluating TGs as a continuous variable (adjusting for baseline TG and HDL-C levels), and regardless of statin treatment. Conclusions: In this post hoc analysis of SUSTAIN 6 and PIONEER 6, over half of patients had elevated TG levels (>151 mg/dL). Semaglutide consistently reduced the risk of MACE vs placebo across baseline TG levels.

Abstract #295 GLP-1 Receptor Agonists and Death From Any Cause in Elderly Patients with Type 2 Diabetes Mellitus: A Post-Hoc Analysis

2018 ◽  
Vol 24 ◽  
pp. 80-81
Author(s):  
Konstantinos Toulis ◽  
Krishna Gokhale ◽  
G. Neil Thomas ◽  
Wasim Hanif ◽  
Krishnarajah Nirantharakumar ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Elderly Patients ◽  
Post Hoc Analysis ◽  
Receptor Agonists ◽  
Post Hoc
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