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Relationship Between Duration of Type 2 Diabetes and Effectiveness of DPP-4 Inhibitor Versus Sulfonylurea as Add-on Therapy: A Post Hoc Analysis.

ABSTRACT: To assess the impact of duration of type 2 diabetes on glucose-lowering effectiveness of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin versus sulfonylureas (SUs) in a real-life setting.Data were extracted from the large 1-year, observational EDGE study (N = 45,868). Patients receiving either DPP-4 inhibitor or any SU as add-on to monotherapy were selected (N = 36,164). Impact of the disease duration on change in glycated hemoglobin (HbA1c) levels was evaluated by using a linear multiple regression model. Descriptive statistics assessed the proportion of patients achieving the composite endpoint (HbA1c <7.0%; 53.0 mmol/mol without hypoglycemia or weight gain), stratified by diabetes duration.At baseline, the overall mean (±SD) type 2 diabetes duration was 5.4 ± 5.24 years, and HbA1c was 8.2 ± 1.33% (66.0 ± 14.5 mmol/mol). HbA1c lowering was directly proportional to the baseline HbA1c (-0.69 per unit; 95% CI -0.696, -0.681; p < 0.0001) and inversely proportional to the disease duration (0.01 per year; 95% CI 0.01, 0.013). There was an increased loss of β-cell function (less pronounced HbA1c drop with increasing disease duration) in patients treated with SU-based regimens (0.025; 95% CI 0.022, 0.027) compared with vildagliptin-based regimens (0.005; 95% CI 0.003, 0.007), with the mean adjusted difference being 0.10 (95% CI -0.122, -0.092; p < 0.0001). Consistently, a higher proportion of patients achieved the composite endpoint with vildagliptin over the diabetes duration (less than 2 to more than 10 years).Vildagliptin demonstrated less dependency on the duration of type 2 diabetes, whereas the effectiveness of SUs diminished faster with increasing duration of the disease in a real-life setting.Novartis Pharma AG.

SUBMITTER: Brath H

PROVIDER: S-EPMC5544613 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:IntroductionENDURE (ClinicalTrials.gov identifier, NCT00856284), a multicenter, double-blind, active-controlled study of 2639 patients with uncontrolled type 2 diabetes mellitus (T2DM), found that metformin in combination with alogliptin (12.5 and 25 mg doses), when compared to standard add-on therapy (sulfonylurea, SU), exerted sustained antihyperglycemic effects over 2 years. This economic analysis of ENDURE aimed to quantify the relationship between increased glycemic durability and cost-effectiveness of alogliptin in the UK clinical setting, and communicate its sustained glycemic benefit in economic terms.MethodsUsing baseline characteristics and treatment effects from the ENDURE trial population, between-group cost-effectiveness analyses compared the combined use of metformin and alogliptin (MET + ALO12.5/25) in patients with inadequately controlled T2DM, as an alternative to metformin and SU (MET + SU). In scenario analyses, an intragroup cost-effectiveness analysis compared MET + ALO12.5/25 with MET + SU; a between-group cost-effectiveness analysis also compared MET + ALO12.5/25 versus MET + SU within a subpopulation of patients who achieved HbA1c control (<7.5%) at 2 years on study drug.ResultsCompared with baseline profiles of patients, combination therapies with alogliptin or SU were associated with improvements in length and quality of life and were cost-effective at established norms. Despite increased drug acquisition costs, alogliptin at 12.5 mg and 25 mg doses resulted in greater predicted lifetime quality-adjusted life year (QALY) gains with associated incremental cost-effectiveness ratios (ICERs) of £10,959/QALY and £7217/QALY compared to SU, respectively.ConclusionThe ENDURE trial and the present cost-effectiveness analysis found that the glycemic durability of alogliptin therapy was associated with improved long-term patient outcomes, QALY gains, and ICERs that were cost-effective when evaluated against standard threshold values. Alogliptin therefore represents a cost-effective treatment alternative to SU as add-on therapy to metformin in patients with poorly managed T2DM.FundingTakeda Development Centre Europe Ltd.

Project description:ObjectiveWe have observed consistent hemodynamic patterns after restoration of spontaneous circulation (ROSC) after ventricular fibrillation (VF) cardiac arrest. We sought to characterize the time-course of these patterns, and to determine whether these differed based on duration of the VF insult.MethodsWe performed a retrospective review of data from a randomized animal experiment that was conducted in an AAALAC-approved animal laboratory. We used mixed-breed domestic swine of either sex. Animals were anesthetized and instrumented for continuous recording of ECG and blood pressures. VF was induced electrically and allowed to progress for various times ranging from brief (22s) to moderate (less than 3 min) to prolonged (3-10 min). All animals were initially shocked (150J) up to three times. If ROSC was not achieved on the three initial shocks, a standardized treatment protocol was followed. We defined cardiovascular collapse as a SBP<90 mmHg sustained for 1 min. For statistical purposes, we classified animals as having VF of <3 min, or >3 min duration. Data were analyzed with Fisher's exact test and survival analysis.ResultsA hyperdynamic phase, consisting of very high-blood pressures and tachycardia, was seen in all animals immediately after ROSC. This lasts from 1 to 4 min. Post-resuscitation cardiovascular collapse occurred in 2/7 (29%) animals in the <3 min group and 13/14 in the >3 min group (93%) p=0.006. Onset of cardiovascular collapse was highly related to duration of VF (log-rank p=0.004).ConclusionsThere are two distinct phases of hemodynamic change after resuscitation of VF. The first phase is a brief hyperdynamic phase. The second phase is either stabilization or cardiovascular collapse. When VF is brief, blood pressures often return to normal without exogenous support. When VF was prolonged animals were rescued with exogenous pressor. Healthcare providers should be prepared to provide pressor support for patients having ROSC after prolonged VF.

Project description:ObjectiveHER-MES was the first head-to-head, phase 4 trial to assess the tolerability and effectiveness of erenumab against standard of care treatment (topiramate). This post hoc analysis compared the efficacy of erenumab with topiramate in patients who completed the trial on study medication.MethodsPost hoc sensitivity analysis was performed using the full analysis set. Outcomes assessed included the proportion of patients with a ≥50% reduction in monthly migraine days (MMD) from baseline (50% responder rate), over the last 3 months (months 4, 5, and 6) of the double-blind treatment phase (DBTP), the 50% responder rate during the first month of the DBTP, and change from baseline in MMD during the DBTP. Multiple imputation was done for efficacy values of patients who discontinued study treatment.ResultsPatients (N = 777) were randomly assigned (1:1) to either 70 or 140 mg/month erenumab (N = 389) or 50-100 mg/day topiramate (N = 388). Of these, 334 patients (85.9%) receiving erenumab, and 231 patients (59.5%) receiving topiramate completed the DBTP on study medication. Patients on study medication until the end of the DBTP received a mean dose of 119 mg/month for erenumab and 92 mg/day for topiramate. At month 1, a significantly greater proportion of patients receiving erenumab (39.2%) reported ≥50% reduction in MMD from baseline compared with those receiving topiramate (24.0%; p < 0.001). In the last 3 months, a significantly larger proportion of patients receiving erenumab (60.3%) achieved ≥50% reduction in MMD from baseline compared with those receiving topiramate (43.3%; p < 0.001). Patients receiving erenumab demonstrated significantly greater reductions in MMD during the last 3 months from baseline versus those receiving topiramate (- 6.13 vs - 4.90; 95% CI: - 1.87 to - 0.61; p < 0.001).ConclusionsThis post hoc analysis demonstrated significantly superior efficacy of erenumab versus topiramate in achieving a ≥50% reduction in MMD with an early onset of efficacy.Trial registrationClinicalTrials.gov NCT03828539 .

Project description:IntroductionAlogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), approved for the treatment of type 2 diabetes mellitus (T2DM). There currently exists no comparative data to support the use of alogliptin in combination with metformin (met) and sulfonylurea (SU). A decision-focused network meta-analysis (NMA) was performed to compare the relative efficacy and safety of alogliptin 25 mg once daily to other DPP-4 inhibitors as part of a triple therapy regimen for patients inadequately controlled on metformin and SU dual therapy.MethodsA systematic literature review was conducted to identify published papers of randomized controlled trials (RCTs) that compared alogliptin with other DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) at their Summary of Product Characteristics (SmPC) recommended daily doses, added on to metformin and SU. Comprehensive comparative analysis involving frequentist meta-analysis and Bayesian NMA compared alogliptin to each DPP-4 inhibitor separately and collectively as a group. Quasi-random effect models were introduced when random effect models could not be estimated.ResultsThe review identified 2186 articles, and 94 full-text articles were assessed for eligibility. Eight RCTs contained appropriate data for inclusion in the NMA. All analyses over all trial population sets produced very similar results, and show that alogliptin 25 mg is as least as effective (as measured by change in HbA1c from baseline, but supported by other outcome measures: change in body weight and FPG from baseline) and safe (as measured by incidence of hypoglycemia and adverse events leading to study discontinuation) as all the other DPP-4 inhibitors in triple therapy.ConclusionThis decision-focused systematic review and NMA demonstrated alogliptin 25 mg daily to have similar efficacy and safety compared to other DPP-4 inhibitors, for the treatment of T2DM in adults inadequately controlled on metformin and SU. (Funded by Takeda Development Centre Americas; EXAMINE ClinicalTrials.gov number, NCT00968708).

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Relationship Between Duration of Type 2 Diabetes and Effectiveness of DPP-4 Inhibitor Versus Sulfonylurea as Add-on Therapy: A Post Hoc Analysis.

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