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

ABSTRACT: Glucagon-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.

SUBMITTER: Sivalingam S

PROVIDER: S-EPMC8134438 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimLiraglutide, a once-daily subcutaneous glucagon-like peptide-1 (GLP-1) agonist, is approved for treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM). For patients with established cardiovascular diseases, liraglutide has also been shown to reduce major cardiovascular events. However, its cost is relatively higher than other oral antidiabetic drugs. This study aims to compare the costs and benefits of liraglutide vs sitagliptin, in treating T2DM in Thailand.MethodsThis study consists of two parts. In part 1, the cost of keeping T2DM under control per patient (HbA1c<7.0% with no reported hypoglycemia and no body weight gain) with liraglutide (1.2 and 1.8 mg daily) was compared with using sitagliptin (100 mg daily). Costs were based on Thai local data. Clinical outcomes were based on head-to-head randomized controlled trials. Part 2 estimated the cost-per-controlled patient, based on major cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, non-fatal stroke). Economic benefit was calculated as the reduction in cardiovascular outcomes.ResultsIn Thailand, liraglutide (1.8 mg daily) costs 7.37-times more than sitagliptin 100 mg. The cost per patient achieving a composite clinical endpoint (HbA1c<7.0%, with no weight gain and no hypoglycemic events) in patients with T2DM receiving liraglutide 1.8 mg is 2.80-times higher than patients receiving sitagliptin 100 mg. When cardiovascular benefits (reduced composite endpoint of major cardiovascular events, ie, cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) were taken into account, it was found that liraglutide had lower cost than sitagliptin, resulting in estimated savings of 20,085 THB (620 USD) per patient per year.ConclusionThe clinical benefits of liraglutide (HbA1c<7.0%, no hypoglycemia, no weight gain, reduced cardiovascular outcomes) partly offset its high price. Therefore, liraglutide should be considered as an appropriate treatment alternative to sitagliptin, particularly for T2DM patients with high cardiovascular risks.

Project description:ObjectivesMetformin is the first-line therapy for most patients with type 2 diabetes, but the majority require treatment intensification at some stage due to the progressive nature of the disease. The 1860-LIRA-DPP-4 trial showed that liraglutide exhibited greater improvements compared with sitagliptin in glycated hemoglobin and body mass index in patients with type 2 diabetes inadequately controlled on metformin monotherapy. As a follow-up to a previously published cost-effectiveness analysis of 1.2 mg liraglutide versus sitagliptin in Spain, the aim of this analysis was to compare long-term projections of the clinical and cost implications associated with 1.8 mg liraglutide and sitagliptin.MethodsFor the modeling analysis, 52-week treatment effect data (as opposed to 26-week data in the previous analysis) were taken from the 1860-LIRA-DPP-4 trial, for adults with type 2 diabetes receiving 1.8 mg liraglutide or 100 mg sitagliptin daily in addition to metformin. Long-term (patient lifetime) projections of clinical outcomes and direct costs (2012 EUR) were made using a published and validated model of type 2 diabetes, with modeling assumptions as per the 1.2 mg liraglutide analysis.ResultsLiraglutide was associated with increased life expectancy (14.24 versus 13.87 years) and quality-adjusted life expectancy [9.24 versus 8.84 quality-adjusted life years (QALYs)] over sitagliptin. Improved clinical outcomes were attributable to the improvement in glycemic control, leading to a reduced incidence of diabetes-related complications, including renal disease, cardiovascular disease, ophthalmic and diabetic foot complications. Liraglutide was associated with increased direct costs (EUR 56,628 versus EUR 52,450), driven by increased pharmacy costs. Based on these estimates, liraglutide was associated with an incremental cost-effectiveness ratio of EUR 10,436 per QALY gained versus sitagliptin.ConclusionsA previous analysis has suggested that 1.2 mg liraglutide is cost-effective from a healthcare payer perspective in Spain, and the present analysis suggests that the 1.8 mg dose is also likely to be cost-effective.

Project description:BackgroundThe prevalence of type 2 diabetes in youth is escalating rapidly. We aimed to evaluate the effects of liraglutide on beta-cell function, metabolic productions of oxidative stress, low grade inflammation compared with metformin in young patients with recent onset type 2 diabetes mellitus.MethodsSixty patients were randomly assigned to receive 8-week liraglutide or metformin treatment. Beta-cell function was assessed by modified beta cell function index (MBCI), early phase of insulin secretion index (?I30/?G30), proinsuin to insulin ratio (P/I) and the insulin area under the curve (AUCins). The expression of 8-OH-dG and 8-iso-PGF2? and hs-C-reactive protein (hs-CRP) were measured as indications of oxidative stress and low grade inflammation.ResultsAfter 8 weeks liraglutide treatment, MBCI, ?I30/?G30, AUCins significantly increased, 8-OH-dG, 8-iso-PGF2?, P/I and hs-CRP remarkably reduced. The differences before and after 8-week liraglutide treatment in ?MBCI (11.1 [2.81, 43.08] vs 0.00 [??8.16, 10.47], P?=?0.017), ?LN?I30/?G30 (0.44 [0.04, 0.85] vs ??0.09 [??0.33, 0.36], P?=?0.049), ?AUCins (117 [??8, 376] vs ??21 [??314, 109] mIU/L, P?=?0.013), ?P/I (??0.05 [??0.09, ??0.03] vs ??0.02 [??0.04, 0.01], P?=?0.026)were remarkably enhanced compared to those of the metformin therapy. The expression of 8-OH-dG, 8-iso-PGF2? and hs-CRP also decreased after 8-week metformin treatment.ConclusionsThese data demonstrated that liraglutide administration was more effective on ameliorating beta-cell function than metformin treatment in young patients with new-onset type 2 diabetes mellitus. Both liraglutide and metformin could alleviate the level of oxidative stress and attenuate low grade inflammatory, we speculate this effect may not the main mechanism of beta-cell function improvement by liraglutide in diabetic patients.Trial registration Chinese Clinical Trials registry, chiCTR1800018008, Registered 27 August 2018—retrospectively registered.Electronic supplementary materialThe online version of this article (10.1186/s13098-018-0392-8) contains supplementary material, which is available to authorized users.

Project description:Anti-inflammatory effects of glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment in T2D may contribute to the cardiovascular benefits observed with GLP-1 RAs in outcome studies. We investigated if the GLP-1 RA liraglutide exerts anti-inflammatory effects through modulation of inflammatory gene expression in peripheral blood mononuclear cells (PBMCs). From 54 participants of a double-blinded trial where individuals with type 2 diabetes (T2D) were randomized to liraglutide (1.8 mg/day) or placebo for 26 weeks, a sub-study was performed in which PBMCs were extracted from fresh blood at study start and at end-of-treatment. The expression of selected inflammatory genes in PBMCs were measured by quantitative real-time polymerase chain reaction (PCR). Moreover, the expression of the GLP-1 receptor (GLP1R) was examined in a subset (n = 40) of the PBMC samples. The human monocytic cell line THP-1 was used for in vitro GLP-1 exposure experiments. The expression of tumor necrosis factor-α (TNFA) (p = 0.004) and interleukin-1β (IL1B) was downregulated (p = 0.046) in the liraglutide-treated group (n = 31), and unchanged in the placebo group (n = 21, p ≥ 0.11), with no significant differences between the two groups (p ≥ 0.67). The expression of interferon-γ (IFNG) and cluster of differentiation 163 (CD163) were upregulated in both groups (p ≤ 0.006) with no differences between groups (p ≥ 0.47). C-C Motif Chemokine Ligand 5 (CCL5) was upregulated in the liraglutide-treated group (p = 0.002) and unchanged in the placebo group (p = 0.14), with no significant difference between groups (p = 0.36). Intercellular adhesion molecule 1 (ICAM1) was unchanged in both groups (p ≥ 0.43). GLP1R expression in the PBMCs was undetectable. In vitro experiments showed no effect of GLP-1 treatment on inflammatory gene expression in THP-1 cells. GLP1R expression in THP-1 cells was not detectable. In summary, we observed a discrete modulatory effect of liraglutide on the expression of inflammatory genes in PBMCs. The lack of evidence for GLP1R expression in PBMCs and THP-1 cells suggests that possible effects of liraglutide on the PBMCs' gene expression are most likely indirect. Further investigations are needed to establish the anti-inflammatory potential of GLP-1 RAs.

Project description:IntroductionThe objective of this study was to compare the clinical effectiveness of liraglutide with sitagliptin and assess the associated economic outcomes in patients with type 2 diabetes mellitus (T2DM) treated in real-world practice in the United States (US).MethodsThis retrospective cohort study used a large US claims database to identify patients with T2DM who initiated liraglutide or sitagliptin between January 2010 and December 2012. Adults (?18 years old) with persistent use of therapy for ?3 months were included. Changes in glycated hemoglobin A1c (A1C) and the proportion of patients achieving A1C targets (?6.5% and <7%) were examined at 6-month follow-up. Diabetes-related total, medical, and pharmacy costs over the follow-up period were assessed. Multivariable regression models were used to estimate the outcomes associated with liraglutide relative to sitagliptin, adjusting for differences in patient demographics and clinical characteristics.ResultsThe study included 1,465 patients with T2DM who initiated liraglutide (N = 376) or sitagliptin (N = 1,089) (mean age [standard deviation (SD)]: 54 [8.9] vs. 58 [10.8] years; 43.9% vs. 61.8% males; both P < 0.01). After controlling for confounding factors, liraglutide patients experienced 0.31% points greater reduction in A1C (0.95% vs. 0.63% points; P < 0.01) at 6-month follow-up than sitagliptin patients and were more likely to reach A1C targets of ?6.5% (odds ratio [OR]: 2.00; P < 0.01) and <7% (OR: 1.55; P < 0.01). Liraglutide patients had $994 lower mean diabetes-related medical costs ($1,241 vs. $2,235; P < 0.01), but $544 higher diabetes-related pharmacy costs ($2,100 vs. $1,556; P < 0.01) during the follow-up. No difference was found in the total mean diabetes-related costs between the two cohorts.ConclusionLiraglutide showed greater improvement in glycemic outcomes than sitagliptin among adult patients with T2DM in real-world clinical practice. Although diabetes-related pharmacy costs for patients using liraglutide were higher compared with sitagliptin, these were offset by significantly lower diabetes-related medical costs, resulting in similar total diabetes-related costs between the two treatment groups.

Project description:INTRODUCTION:This study compared the clinical and economic outcomes of long-term use of liraglutide versus sitagliptin for the treatment of type 2 diabetes (T2DM) in real-world practice in the USA. METHODS:We identified adult patients (≥ 18 years old) with T2DM who initiated liraglutide or sitagliptin in 2010-2014 using a large claims database. Quarterly glycemic control measures and annual healthcare costs were assessed during the 1st and 2nd years of persistent medication use. Their associations with medication use (liraglutide or sitagliptin) were estimated using multivariable regression models adjusted for patient demographic and clinical characteristics. RESULTS:A total of 3113 patients persistently used liraglutide (N = 493) or sitagliptin (N = 2620) for ≥ 1 year [mean age (standard deviation, SD): 53 (8.5) vs. 56 (9.7) years; 48.3% vs. 62.3% males; both p < 0.05]; 911 (including 113 liraglutide users) were persistent users for ≥ 2 years. During the 1st-year follow-up, liraglutide users (versus sitagliptin users, after adjustment) experienced larger glycated hemoglobin (HbA1c) reductions from baseline (ranging from 0.34%-point in quarter 1 to 0.21%-point in quarter 4); higher likelihoods of obtaining HbA1c reductions of ≥ 1%-points or ≥ 2%-points [odds ratios (ORs) range 1.47-2.04]; and higher likelihoods of reaching HbA1c goals of < 6.5% or < 7% (ORs range 1.51-2.12) (all p < 0.05). Liraglutide users also experienced HbA1c reductions from baseline in the 2nd-year follow-up (0.53-0.33%-point, all p < 0.05). Although liraglutide users incurred higher healthcare costs than sitagliptin users during the 1st-year follow-up, they had $2674 (per patient) lower all-cause medical costs (adjusted cost ratio: 0.67, p < 0.05) and similar total costs (all-cause and diabetes-related) in the 2nd year. CONCLUSION:Long-term use of liraglutide for 1 or 2 years was associated with better glycemic control than using sitagliptin. Savings in medical costs were realized for liraglutide users during the 2nd year of persistent treatment, which offset differences in pharmacy costs. FUNDING:Novo Nordisk Inc.

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

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