Health and Productivity Benefits with Early Intensified Treatment in Patients with Type 2 Diabetes: Results from Korea.

The available evidence suggests positive health outcomes associated with early treatment intensification in Type 2 diabetes mellitus (T2DM). Our study estimated the productivity effects arising from improved health correlated with early intensified treatment in T2DM in Korea. Using a recently published methodology and model, we investigated the association between early intensified treatment and the probability of experiencing fewer diabetes-related complication events. Treatment strategies leading to better health outcomes are expected to be associated with social value through increased participation in paid and unpaid work activities. Therefore, we translated the lower incidence of complications into monetary terms related to productivity for the Korean population. We quantified productivity by considering (a) absenteeism, (b) presenteeism, (c) permanent loss of labor force, and (d) activity restriction. Deterministic and probabilistic sensitivity analyses in the base case parameter were performed. Approximately, 1.7 thousand (standard deviation [SD] ±580 events) micro- and macrovascular complication events could potentially be avoided by early treatment intensification. This led to a societal gain attributed to increased productivity of 23 million USD (SD ± $8.2 million). This article demonstrates the likelihood of achieving better health and productivity through early intensified treatment in diabetes.

The societal impact of early intensified treatment in patients with type 2 diabetes mellitus.

Aim: The current study estimates the societal impact of early intensified treatment compared with initial monotherapy with subsequent treatment intensification in newly diagnosed adults with type 2 diabetes mellitus in Mexico. Methods: An individual patient-level simulation and a static cohort model were employed to simulate the treatment pathway and the probability of experiencing complications of diabetes. The avoided number of events was translated into avoided productivity losses, which were monetized using wages. Results: Patients on early intensified treatment experienced approximately 13,000 fewer complication events over 10 years. This was translated into a societal impact of $54 million (USD). Conclusion: Early treatment intensification is likely to be of particular benefit to health outcomes and productivity losses.

Effect of angiotensin receptor blockers on blood pressure and renal function in patients with concomitant hypertension and chronic kidney disease: a systematic review and meta-analysis.

Objective: Angiotensin receptor blockers (ARB) are among the recommended first-line treatment options in patients with hypertension and chronic kidney disease (CKD). This meta-analysis evaluated the effect of ARB on blood pressure (BP) and renal function in patients with concomitant hypertension and CKD with or without diabetes.Methods: Literature search was performed in PubMed/MEDLINE, EMBASE and BIOSIS to identify parallel-group, randomized controlled trials (≥8 weeks) reporting the effects of ARB on office systolic/diastolic BP (SBP/DBP), estimated glomerular filtration rate (eGFR), serum creatinine (SCr), creatinine clearance (CrCl) or proteinuria in adults with hypertension and CKD. Mean difference (MD, generic inverse variance) with 95% confidence intervals (CIs) was used to report an outcome.Results: Among the 24 studies identified, 19 evaluated ARB as monotherapy, 4 evaluated ARB as combination therapy and one evaluated ARB both as monotherapy and combination therapy. Median (range) duration of the studies was 12 (1.84-54.0) months. ARB monotherapy significantly (p < 0.01) reduced BP (treatment ≥1 year: SBP [MD: -14.84 mmHg; 95% CI: -17.82 to -11.85]/DBP [-10.27 mmHg; -12.26 to -8.27]) and proteinuria (≥1 year [-0.90 g/L; -1.22 to -0.59]). Results were consistent for combination therapy. In these studies, non-significant changes were observed for eGFR, CrCl and SCr. The impact of SBP changes on eGFR was not significant; however, studies were of a relatively short duration.Conclusion: ARB had a favorable impact on BP and renal parameters such as proteinuria with monotherapy as well as with combination therapy, highlighting their potential benefits in patients with hypertension and CKD. During the short follow-up of these studies, no significant change in eGFR was observed.

A pre-specified statistical analysis plan for the VERIFY study: Vildagliptin efficacy in combination with metformin for early treatment of T2DM.

AIMS: To ensure the integrity of the planned analyses and maximize the clinical utility of the VERIFY study results by describing the detailed concepts behind its statistical analysis plan (SAP) before completion of data collection and study database lock. The SAP will be adhered to for the final primary data analysis of the VERIFY trial. MATERIALS AND METHODS: Vildagliptin efficacy in combination with metformin for early treatment of T2DM (VERIFY) is an ongoing, multicentre, randomized controlled trial aiming to demonstrate the clinical benefits of glycaemic durability and glucose control achieved with an early combination therapy in newly-diagnosed type 2 diabetes (T2DM) patients. RESULTS: The SAP was initially designed at the study protocol conception phase and later modified, as reported here, in collaboration between the steering committee members, statisticians, and the VERIFY study leadership team. All authors were blinded to treatment allocation. An independent statistician has additionally retrieved and presented unblinded data to the independent data safety monitoring committee. An overview of the trial design with a focus on describing the fine-tuning of the analysis plan for the primary efficacy endpoint, risk of initial treatment failure, and secondary, exploratory and pre-specified subgroup analyses is provided here. CONCLUSION: According to optimal trial practice, the details of the statistical analysis and data-handling plan prior to locking the database are reported here. The SAP accords with high-quality standards of internal validity to minimize analysis bias and will enhance the utility of the reported results for improved outcomes in the management of T2DM.

Re: Association Between Renal Dysfunction and Major Adverse Cardiac Events After Liver Transplantation: Evidence From an International Randomized Trial of Everolimus-Based Immunosuppression.

Ann Transplant. 2018 Oct 26;23:751-757. doi: 10.12659/AOT.911030. PMID: 30361470, PMCID: PMC6248043 In the paper, the sentence on page 754, first column, lines 4, 5, and 6 has been incorrectly written:  At the month 24 study visit, mean (SD) eGFR was 74.7 (26.1), 67.8 (21.0), and 77.5 (26.2) mL/min/1.73 m2 in the EVR/rTAC, TAC Elimination, and TAC Control groups, respectively (p=0.007). The corrected sentence should read:  At the 24-month study visit, mean (SD) eGFR was 74.7 (26.1), 67.8 (21.0), and 77.5 (26.2) mL/min/1.73 m2 in the EVR/rTAC, TAC Control, and TAC Elimination groups, respectively (p=0.007).

Association Between Renal Dysfunction and Major Adverse Cardiac Events After Liver Transplantation: Evidence from an International Randomized Trial of Everolimus-Based Immunosuppression.

BACKGROUND Prospective evidence is lacking regarding the association between renal dysfunction and cardiovascular events after liver transplantation. MATERIAL AND METHODS Data were analyzed post hoc regarding renal function and major adverse cardiac events in a two-year prospective trial of de novo liver transplant recipients randomized at 30 days post-transplant to (i) everolimus [EVR]/reduced tacrolimus [EVR/rTAC] (ii) EVR with tacrolimus discontinued [TAC Elimination] or (iii) standard tacrolimus [TAC Control]. RESULTS By month 24 post-transplant, 32/716 patients had experienced a first major cardiac event (4.5%): 4.1% (10/245), 2.2% (5/229) and 7.0% (17/242) of patients in the EVR/rTAC, TAC Elimination and TAC Control groups, respectively (p=0.043). The cumulative eGFR area under the curve (AUC) from randomization to month 24 was 119 706, 123 082, and 105 946 mL in the EVR/rTAC, TAC Elimination, and TAC Control groups, respectively, corresponding to a mean eGFR AUC of 82.4, 83.0, and 71.9 mL/min/1.73 m². Cox regression modeling showed that mean eGFR AUC was inversely associated with time to first major cardiac event: the hazard ratio per mL/min/1.73 m² was -0.0000015 [95% CI -0.00000078; -0.0000024] (p<0.001). CONCLUSIONS These findings confirm retrospective evidence that the risk of major cardiac events increases with deteriorating renal function after liver transplantation and demonstrate the need for careful cardiovascular risk management in patients with renal impairment. Immunosuppression based on everolimus with tacrolimus withdrawal, or to a lesser extent tacrolimus reduction, improves both renal function and the risk of major cardiac events compared to standard tacrolimus therapy in liver transplant recipients.

Comparison of glycopyrronium versus tiotropium on the time to clinically important deteriorations in patients with COPD: a post-hoc analysis of randomized trials.

Glycopyrronium is a once-daily, inhaled long-acting muscarinic antagonist (LAMA) demonstrating similar efficacy to inhaled tiotropium in patients with moderate-to-severe COPD; however, the benefit of LAMAs on COPD symptoms has been variable. COPD is a progressive disease in which many patients develop an acute or sustained deterioration. Data on the prevention of clinically important deteriorations (CID) using LAMAs are limited. A pooled analysis was performed on four Phase III trials (n = 2936) that compared the efficacy of glycopyrronium (n = 1859) with tiotropium (n = 1077). The primary endpoint was significant delay and/or reduction in the occurrence of CID. CID was defined as any of the following: ≥100 mL decrease from baseline in pre-dose forced expiratory volume in 1 second (FEV1), ≥4 point increase in St George's Respiratory Questionnaire score or a moderate-to-severe COPD exacerbation occurring after the first dose of study medication. A sustained CID was a CID occurring on ≥2 consecutive visits 4 weeks apart or for ≥50% of all available subsequent visits. Baseline characteristics for the overall population were similar. Patients had moderate (62%) or severe (38%) COPD. Mean post-bronchodilator FEV1 was approximately 55% predicted, and mean FEV1 reversibility was 16.7 and 18.6% in the glycopyrronium and tiotropium groups, respectively. Both glycopyrronium and tiotropium significantly reduced time to CID and sustained CID versus placebo (p < 0.001). No statistically significant differences were found between the glycopyrronium and tiotropium treatment groups in time to CID or sustained CID. Glycopyrronium is effective in delaying time to clinically important deteriorations, with similar efficacy to tiotropium.

Efficacy and effectiveness of valsartan/amlodipine and valsartan/amlodipine/hydrochlorothiazide in hypertension: randomized controlled versus observational studies.

OBJECTIVE: The aim of this post-hoc analysis was to compare the results from randomized controlled trials (RCTs) and real-world evidence (RWE) studies of valsartan/amlodipine (Val/Aml) and valsartan/amlodipine/hydrochlorothiazide (Val/Aml/HCTZ) in patients with uncontrolled hypertension (>140/90 mmHg). METHODS: Data was pooled from 15 RCTs (N = 5542) and 8 RWE studies (N = 1397) for Val/Aml; and 2 RCTs (N = 804) and 5 RWE studies (N = 9380) for Val/Aml/HCTZ. Patients who received Val/Aml (80/5, 160/5, 160/10, 320/5, or 320/10 mg), Val/Aml/HCTZ (160/5/12.5, 160/5/25, 160/10/12.5, 160/10/25, or 320/10/25 mg) or placebo were considered for this analysis. Only patients with both baseline and follow-up assessment within 60-90 days after baseline had been included in the analysis. Patients with missing values were excluded from the analysis. Using fitted linear mixed-effects model and random factors, treatment interactions and study design with mean sitting systolic blood pressure (msSBP), diastolic BP (msDBP) and pulse pressure (msPP) reductions from baseline to Week 8-12 of treatment were compared. RESULTS: Baseline demographics and patient characteristics were comparable between RCT and RWE datasets and within Val/Aml and Val/Aml/HCTZ treatment groups. In both RCT and RWE studies, least-squares mean (LSM) reduction in msSBP/msDBP and msPP from baseline were significant (p < .05) across all dosages. The efficacy of Val/Aml in RCTs was statistically significantly greater than in RWE studies for msSBP/msDBP (-23.1/-13.8 vs. -17.9/-9.1 mmHg) but the difference was non-significant for msPP (-8.6 vs. -9.3 mmHg; p = .77). For Val/Aml/HCTZ, no direct comparison was available but a similar trend was observed. The difference observed for msSBP and msDBP may be due to routine practice setting, larger populations may have more confounders and different behaviors towards treatment adherence. CONCLUSION: These findings demonstrate that the efficacy of Val/Aml and Val/Aml/HCTZ in RCTs was more pronounced compared with their effectiveness in RWE studies in different ethnic populations although the overall benefit was not different.

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 ß-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). CONCLUSION: 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. FUNDING: Novartis Pharma AG.

The effect of indacaterol/glycopyrronium versus tiotropium or salmeterol/fluticasone on the prevention of clinically important deterioration in COPD.

BACKGROUND: Endpoints that evaluate deterioration rather than improvement of disease may have clinical utility in COPD. In this analysis, we compared the effects of different maintenance treatments on the prevention of clinically important deterioration (CID) in moderate-to-severe COPD patients. METHODS: Data were analyzed from three 26-week studies comparing indacaterol/glycopyrronium (IND/GLY) with tiotropium (TIO) or salmeterol/fluticasone (SFC). Two definitions of CID were used; each was a composite of three outcome measures typically associated with COPD. Definition 1 (D1) comprised a ≥100 mL decrease in forced expiratory volume in 1 second (FEV1), a ≥4-unit increase in St George's Respiratory Questionnaire, and a moderate-to-severe COPD exacerbation. In Definition 2 (D2), a ≥1-unit decrease in transition dyspnea index replaced FEV1. RESULTS: Using D1, IND/GLY significantly reduced the risk of first or sustained CID versus either TIO (hazard ratio 0.72 [0.61, 0.86], P=0.0003 and 0.73 [0.61, 0.89], P=0.001) or SFC (0.67 [0.57, 0.80] and 0.63 [0.52, 0.77], both P<0.0001). With D2, IND/GLY significantly reduced the risk of first, but not sustained, CID versus TIO (0.80 [0.64 to 0.99], P=0.0359 and 0.85 [0.66, 1.10], P=0.2208) and both first and sustained CID versus SFC (0.73 [0.61, 0.88], P=0.001 and 0.72 [0.58, 0.90], P=0.0036). CONCLUSION: These data confirm the utility of the CID endpoint as a means of monitoring COPD worsening in patients with moderate-to-severe COPD. Using the CID measure, we demonstrated that dual bronchodilation with IND/GLY significantly reduced the risk of CID versus either long-acting muscarinic antagonist or long-acting ß2-agonist/inhaled corticosteroid treatment, providing further evidence for the benefit of dual bronchodilation in this patient population.

LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as ß2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD. METHODS: This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks' LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Eighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P<0.0001), with patients more likely to achieve clinically important improvements in FEV1 of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George's Respiratory Questionnaire scores at week 12 versus LAMA (both P<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 and P=0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]). CONCLUSION: The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use.

Indacaterol/glycopyrronium in symptomatic patients with COPD (GOLD B and GOLD D) versus salmeterol/fluticasone: ILLUMINATE/LANTERN pooled analysis.

BACKGROUND: Indacaterol/glycopyrronium (IND/GLY) is approved for maintenance treatment of adult patients with COPD. This post hoc analysis explored the efficacy and safety of IND/GLY versus salmeterol/fluticasone (SFC) in symptomatic (Global Initiative for Chronic Obstructive Lung Disease [GOLD] B and GOLD D) patients with moderate-to-severe COPD. PATIENTS AND METHODS: Data from LANTERN and ILLUMINATE studies were pooled and analyzed. In both studies, symptomatic COPD patients were randomized to once-daily IND/GLY 110 µg/50 µg or twice-daily SFC 50 µg/500 µg. End points were pre-dose trough forced expiratory volume in one second (FEV1), standardized area under the curve for FEV1 from 0 to 12 hours (FEV1 AUC0-12 hours), peak FEV1, peak forced vital capacity (FVC), pre-dose trough FVC, Transition Dyspnea Index (TDI) total score, St George's Respiratory Questionnaire total score, rescue medication use and safety. RESULTS: A total of 1,263 patients were classified as either GOLD B (n=809) or GOLD D (n=454). At week 26, IND/GLY demonstrated statistically significant improvement in all lung function parameters versus SFC in patients in both the GOLD B and GOLD D subgroups. TDI total score and rescue medication use were significantly improved with IND/GLY versus SFC in the overall population and in the GOLD B (TDI total score only) and GOLD D (rescue medication only) subgroups. IND/GLY also reduced the rate of exacerbations in the pooled population. Overall safety profile was comparable with a higher incidence of pneumonia in the SFC-treated group. CONCLUSION: In this pooled analysis, IND/GLY demonstrated superior efficacy compared with SFC in patients in the GOLD B and GOLD D subgroups and supported its use in symptomatic COPD patients.

Effects of treatment withdrawal on brachial and central aortic pressure after direct renin inhibition or angiotensin receptor blockade.

INTRODUCTION: Whilst sustained lowering of brachial systolic blood pressure (Br-SBP) and central aortic systolic pressure (CASP) have been demonstrated in patients with hypertension, effects of treatment withdrawal on these parameters have not been investigated. The ASSERTIVE study previously reported more sustained control of Br-SBP with aliskiren versus telmisartan in patients with hypertension, following 7-days treatment withdrawal. In this ASSERTIVE sub-study, we hypothesised that aliskiren would similarly exert more sustained control of CASP than telmisartan during treatment withdrawal. METHODS: We investigated the effects of treatment withdrawal on both Br-SBP and CASP following 12-weeks treatment with either aliskiren (300 mg) or telmisartan (80 mg). Br-SBP and CASP were measured at the end of treatment, and at days 2 and 7 following treatment withdrawal in 303 patients (CASP randomised set). RESULTS: Of the CASP randomised set, 94 patients completed CASP measurements at all time points (CASP completer set). After 7 days of treatment withdrawal, aliskiren demonstrated lesser increases in both Br-SBP and CASP than telmisartan; Br-SBP change: -2.0±1.6 vs. +5.6±1.7 mmHg, p = 0.001; CASP change: -0.4±1.6 vs. +4.6±1.7 mmHg, p = 0.041, n = 94. Similar findings were obtained for the CASP randomised set. CONCLUSIONS: Following treatment withdrawal, aliskiren demonstrated more sustained control of both brachial and central SBP than telmisartan.

Effectiveness and tolerability of second-line treatment with vildagliptin versus other oral drugs for type 2 diabetes in a real-world setting in the Middle East: results from the EDGE study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic progressive disease that requires treatment intensification with antihyperglycemic agents due to progressive deterioration of ß-cell function. A large observational study of 45,868 patients with T2DM across 27 countries (EDGE) assessed the effectiveness and safety of vildagliptin as add-on to other oral antidiabetic drugs (OADs) versus other comparator OAD combinations. Here, we present results from the Middle East countries (Bahrain, Jordan, Kuwait, Lebanon, Oman, Palestine, and the United Arab Emirates). METHODS: Patients inadequately controlled with OAD monotherapy were eligible after the add-on treatment was chosen by the physician based on clinical judgment and patient need. Patients were assigned to either vildagliptin or comparator OADs (sulfonylureas, thiazolidinediones, glinides, α-glucosidase inhibitors, or metformin, except incretin-based therapies) based on the add-on therapy. The primary endpoint was the proportion of patients achieving a glycated hemoglobin (HbA1c) reduction of >0.3% without peripheral edema, hypoglycemia, discontinuation due to a gastrointestinal event, or weight gain≥5%. One of the secondary endpoints was the proportion of patients achieving HbA1c<7% without hypoglycemia or weight gain. Change in HbA1c from baseline to study endpoint and safety were also assessed. RESULTS: Of the 4,780 patients enrolled in the Middle East, 2,513 received vildagliptin and 2,267 received other OADs. Overall, the mean (±standard deviation) age at baseline was 52.1±10.2 years, mean HbA1c was 8.5%±1.3%, and mean T2DM duration was 4.2±4.0 years. The proportion of patients achieving the primary (76.1% versus 61.6%, P<0.0001) and secondary (54.8% versus 29.9%, P<0.0001) endpoints was higher with vildagliptin than with the comparator OADs. The unadjusted odds ratios for the primary and secondary endpoints were 1.98 (95% confidence interval 1.75-2.25) and 2.8 (95% confidence interval 2.5-3.2), respectively, in favor of vildagliptin. Vildagliptin achieved a numerically greater reduction in HbA1c (1.7%) from baseline versus comparator OADs (1.4%). The overall incidence of adverse events was comparable between studied cohorts. CONCLUSION: In real life, treatment with vildagliptin was associated with a higher proportion of patients with T2DM achieving better glycemic control without tolerability issues in the Middle East.

Changes in body weight after 24 weeks of vildagliptin therapy as a function of fasting glucose levels in patients with type 2 diabetes.

BACKGROUND: In order to test the hypothesis that the degree of weight change with the dipeptidyl peptidase-4 inhibitor vildagliptin is dependent on the level of glycemic control at baseline, the weight changes from pooled monotherapy studies after 24 weeks of therapy with vildagliptin were assessed versus the fasting plasma glucose (FPG) levels at baseline. METHODS: Data were pooled from eight clinical monotherapy trials including 2,340 previously drug-naïve patients with type 2 diabetes mellitus who received vildagliptin monotherapy (50 mg once daily [n=359] or 50 mg twice daily [n=1,981]). The trials were all randomized, double-blind, controlled clinical trials with a prespecified week 24 study visit. RESULTS: Linear regression analysis of weight change after 24 weeks relative to baseline FPG showed an intercept of -2.259 kg (95% confidence interval -2.86, -1.66; P<0.0001) and a positive slope of 0.1552 kg (95% confidence interval 0.10-0.21; P<0.0001). Neutral caloric balance (no weight change) was observed at a FPG of 14.6 mmol/L (263 mg/dL). Baseline FPG values below and above this threshold were associated with weight loss and weight gain, respectively. For instance, from this analysis, a baseline FPG of 8 mmol/L (144 mg/dL) predicts a weight loss of 1 kg. CONCLUSION: The present analysis showed that treatment with vildagliptin results in a negative caloric balance when glucose levels are below the renal threshold at baseline.

Efficacy of vildagliptin versus sulfonylureas as add-on therapy to metformin: comparison of results from randomised controlled and observational studies.

AIMS/HYPOTHESIS: Randomised control trials (RCTs) do not always reflect real-life outcomes for glucose-lowering drugs. In this work we compared RCT and real-life data on the efficacy of the dipeptidyl peptidase-IV (DPP-4) inhibitor vildagliptin or sulfonylureas when added to metformin. METHODS: Data were pooled from five RCTs examining vildagliptin (n = 2,788) and sulfonylureas (glimepiride [n = 1,259] or gliclazide [n = 433]), added to metformin. For real-life conditions, data were extracted from an observational study examining vildagliptin (n = 7,002) or sulfonylureas (n = 3,702), added to metformin monotherapy. Linear regression analyses were performed between the baseline HbA1c and the change in HbA1c (Δ HbA1c) after 24 weeks. RESULTS: Baseline HbA1c correlated to Δ HbA1c (r (2) = 0.36, slope = -0.54 [95% CI -0.55, -0.53; p < 0.0001]) for both treatments. With sulfonylureas, the slope of the correlation was steeper in the observational study than in RCTs (interaction coefficient = -0.327, p < 0.001), whereas for vildagliptin, the slope was virtually identical in the observational study and the RCTs (interaction coefficient = 0.024, p = 0.175). For any given baseline HbA1c, Δ HbA1c with sulfonylureas was smaller in real life than in RCTs, whereas Δ HbA1c with vildagliptin was the same. CONCLUSIONS/INTERPRETATIONS: When comparing RCT to real-life data, the decrease in HbA1c from baseline with sulfonylurea treatment is smaller in real life than in RCTs, whereas the reduction with vildagliptin is essentially the same, suggesting that the full power of treatment is retained in real life for vildagliptin but not for sulfonylureas, possibly due to fear of hypoglycaemia.

Real-life effectiveness and tolerability of vildagliptin and other oral glucose-lowering therapies in patients with type 2 diabetes in Germany.

INTRODUCTION: Metformin is an established first-line treatment for patients with type 2 diabetes mellitus (T2DM), but treatment intensification with other oral antidiabetes drugs (OADs) is usually required over time. Effectiveness of diabetes control with vildagliptin and vildagliptin/metformin was a 1-year, large observational study of 45,868 patients with T2DM across 27 countries which assessed effectiveness and safety of vildagliptin as add-on therapy to other OADs versus other comparator OAD combinations. Here, we present the data from Germany. METHODS: Patients inadequately controlled with monotherapy were eligible only after the add-on treatment was finalized. Patients were assigned to either vildagliptin or comparator OADs [sulfonylureas, thiazolidinediones, glinides, α-glucosidase inhibitors or metformin, excluding dipeptidyl peptidase 4 (DPP-4) inhibitors or glucagon-like peptide-1 mimetic/analogues]. The primary efficacy endpoint was the proportion of patients achieving a glycosylated hemoglobin (HbA1c) reduction of >0.3% without peripheral edema, hypoglycemia, discontinuation due to a gastrointestinal event or weight gain ≥5%. One secondary efficacy endpoint was the proportion of patients achieving HbA1c <7% without hypoglycemia and weight gain. Change in HbA1c from baseline to study endpoint and safety were assessed. RESULTS: Of 8,887 patients enrolled in Germany, 6,679 received vildagliptin and 1,695 received other OADs. The mean ± SD baseline age, HbA1c, and T2DM duration were 62.8 ± 11.0 years, 7.7 ± 1.2%, and 5.8 ± 4.9 years, respectively. The proportion of patients achieving the primary (34.5% vs. 30.5%, p < 0.01) and secondary (25.4% vs. 21.7%, p = 0.01) endpoints was higher with vildagliptin than comparator OADs. Vildagliptin showed a numerically greater reduction in HbA1c (0.7%) from baseline vs. comparator OADs (0.6%). The overall incidence of adverse events was similar. CONCLUSION: In real life, treatment with vildagliptin is associated with a higher proportion of patients reaching target HbA1c without hypoglycemia and weight gain compared with other OADs in Germany.

Vildagliptin more effectively achieves a composite endpoint of HbA1c < 7.0% without hypoglycaemia and weight gain compared with glimepiride after 2 years of treatment.

This post hoc analysis reports that overall proportion of patients achieving a composite endpoint of HbA1c<7.0% (<53.0 mmol/mol) without hypoglycaemia and weight gain was higher with vildagliptin than glimepiride after 2 years in type 2 diabetes patients inadequately controlled on metformin monotherapy, regardless of age and duration of diabetes.

Demonstrating the burden of hypoglycemia on patients' quality of life in diabetes clinical trials: measurement considerations for hypoglycemia.

OBJECTIVES: To evaluate the association between hypoglycemia and health-related quality of life (HRQoL) in the context of a clinical trial using both an objectively confirmed and a patient-reported measure of hypoglycemia. METHODS: During a phase III, double-arm, randomized study, patients completed the short form 36 health survey (SF-36), a generic HRQoL questionnaire, at baseline and at weeks 24, 52, and 104. The objectively confirmed measure of hypoglycemia was based on a combination of plasma glucose measure and presence of hypoglycemia-related symptoms. The patient-reported frequency of hypoglycemia was defined as the following item: "How often have you felt that your blood sugars have been unacceptably low recently?" The association between hypoglycemia and HRQoL was evaluated in intent-to-treat patients (N = 3059) by using repeated-measurements analyses, with SF-36 scores used as explained variables and baseline SF-36 score, age, sex, country, time, and either number of objectively confirmed hypoglycemic events (0, ≥1) or patient-reported frequency of hypoglycemia (continuous variable 0-6) as explanatory variables. RESULTS: During study duration, less than 6% of patients experienced at least one objectively confirmed hypoglycemic event and about half the patients reported unacceptably low blood sugars "none of the time." The association between the number of objectively confirmed hypoglycemic events and HRQoL was not statistically significant, while the patient-reported frequency of hypoglycemia was statistically significantly related to all SF-36 scores (P < 0.001), except physical functioning; patients reporting greater perceived frequency of hypoglycemia had worse HRQoL. CONCLUSIONS: Using a patient-reported measure of hypoglycemia in the context of a clinical trial could enable the burden of hypoglycemia for patients to be demonstrated.