Effectiveness and cost-effectiveness of six GLP-1RAs for treatment of Chinese type 2 diabetes mellitus patients that inadequately controlled on metformin: a micro-simulation model.

Objective: To systematically estimate and compare the effectiveness and cost-effectiveness of the glucagon-like peptide-1 receptor agonists (GLP-1RAs) approved in China and to quantify the relationship between the burden of diabetic comorbidities and glycosylated hemoglobin (HbA1c) or body mass index (BMI). Methods: To estimate the costs (US dollars, USD) and quality-adjusted life years (QALY) for six GLP-1RAs (exenatide, loxenatide, lixisenatide, dulaglutide, semaglutide, and liraglutide) combined with metformin in the treatment of patients with type 2 diabetes mellitus (T2DM) which is inadequately controlled on metformin from the Chinese healthcare system perspective, a discrete event microsimulation cost-effectiveness model based on the Chinese Hong Kong Integrated Modeling and Evaluation (CHIME) simulation model was developed. A cohort of 30,000 Chinese patients was established, and one-way sensitivity analysis and probabilistic sensitivity analysis (PSA) with 50,000 iterations were conducted considering parameter uncertainty. Scenario analysis was conducted considering the impacts of research time limits. A network meta-analysis was conducted to compare the effects of six GLP-1RAs on HbA1c, BMI, systolic blood pressure, and diastolic blood pressure. The incremental net monetary benefit (INMB) between therapies was used to evaluate the cost-effectiveness. China's per capita GDP in 2021 was used as the willingness-to-pay threshold. A generalized linear model was used to quantify the relationship between the burden of diabetic comorbidities and HbA1c or BMI. Results: During a lifetime, the cost for a patient ranged from USD 42,092 with loxenatide to USD 47,026 with liraglutide, while the QALY gained ranged from 12.50 with dulaglutide to 12.65 with loxenatide. Compared to exenatide, the INMB of each drug from highest to lowest were: loxenatide (USD 1,124), dulaglutide (USD -1,418), lixisenatide (USD -1,713), semaglutide (USD -4,298), and liraglutide (USD -4,672). Loxenatide was better than the other GLP-1RAs in the base-case analysis. Sensitivity and scenario analysis results were consistent with the base-case analysis. Overall, the price of GLP-1RAs most affected the results. Medications with effective control of HbA1c or BMI were associated with a significantly smaller disease burden (p < 0.05). Conclusion: Loxenatide combined with metformin was identified as the most economical choice, while the long-term health benefits of patients taking the six GLP-1RAs are approximate.

Evaluación clínica y económica de análogos del GLP-1 para el tratamiento del sobrepeso / Clinical and economic evaluation of GLP-1 analogues for the treatment of overweight

CONTEXTO: El sobrepeso y la obesidad constituyen un importante problema de salud pública en todo el mundo. El tratamiento inicial consta de modificación del estilo de vida (LSM, por sus siglas en inglés) y en caso de falla, se inicia con tratamiento farmacológico como semaglutida, la cual está aprobada por agencias regulatorias internacionales y nacionales para el sobrepeso con un IMC de ≥ 25 kg/m2 a ≤ 29.9 kg/m2 y la obesidad con un IMC ≥ 30 kg/m2. El objetivo de este informe es revisar la eficacia clínica, la seguridad y la costo-efectividad de semaglutida en comparación con liraglutida para el tratamiento del sobrepeso y obesidad en la población en edad adulta sin Diabetes Mellitus tipo 2 (DM2). Ambos medicamentos cuentan con registro sanitario expedido por la Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS) para el tratamiento del sobrepeso y obesidad en la población en edad adulta, así como para el tratamiento de la DM2; sin embargo, en el Compendio Nacional de Insumos para la Salud (CNIS), se encuentran disponibles solamente para el tratamiento de la población en edad adulta con DM2. MÉTODOS: Se realizó una búsqueda sistemática de la literatura en diversas bases de datos. Se seleccionaron 13 documentos relevantes (2 revisiones sistemáticas [RS] con metanálisis en red [NMA, por sus siglas en inglés], 5 ensayos clínicos aleatorios [ECAs], 3 evaluaciones económicas y 3 evaluaciones de tecnologías para la salud). Las medidas de resultado fueron el cambio del peso corporal, porcentaje de eventos adversos (EAs), costos y la razón costo-efectividad incremental (RCEI). RESULTADOS: En la RS con NMA de Smith et al. (2022)2 , los resultados mostraron que, en pacientes en edad adulta con sobrepeso y obesidad, sin DM2 y con LSM, la diferencia porcentual del cambio en el peso desde el estado basal con semaglutida versus liraglutida fue de -7.02 (intervalo de confianza [IC] del 95%: - 9.61 a -4.41, 23 de 32 puntos del PRISMA NMA con un riesgo de sesgo alto) y con respecto a placebo, la diferencia porcentual fue de -12.43 (IC del 95%: -14.51 a -10.38). Los resultados para la RS con NMA de Vosoughi et al. (2021)3 , en esta misma población, indica que la diferencia de medias (DM) del cambio en el peso desde el estado basal con semaglutida versus liraglutida fue de -5.53 (IC del 95%: -7.45 a - 3.60, en 4 estudios, 52 semanas de seguimiento, con 29 de 32 puntos del PRISMA NMA con un riesgo de sesgo alto) y en la escala SUCRA semaglutida obtuvo una clasificación del 100%, lo que indica que refleja una mayor probabilidad de ser más efectiva en términos de pérdida de peso y con una menor probabilidad de presentar EAs. CONCLUSIONES: Los 5 ECAs4­8 , concluyeron que semaglutida, a una dosis de mantenimiento de 2.4 mg, presentó mayor eficacia frente a liraglutida 3.0 mg (dosis de mantenimiento) y placebo, y con una seguridad similar a la esperada en el grupo de los análogos del péptido similar al glucagón tipo 1 (GLP-1). En dos evaluaciones económicas9,10 se indicó que semaglutida fue costo-efectiva versus sus respectivos comparadores. En Kim et al. (2022) 9 los comparadores utilizados fueron ningún tratamiento, dieta y ejercicio (D&E), liraglutida 3.0 mg, fentermina/topiramato y naltrexona/bupropión; mientras que en Olivieri et al. (2022) 10 los comparadores considerados fueron D&E sola, liraglutida 3.0 mg, orlistat y naltrexona 32 mg/bupropión. Sin embargo, un tercer estudio11 mostró que semaglutida no fue costo-efectiva dados los umbrales de disposición a pagar aceptados. Los hallazgos deben interpretarse con cautela considerando las limitaciones tanto clínicas como económicas. Se requieren más estudios de semaglutida que investiguen sobre los efectos a largo plazo, estudios directos versus otras opciones de tratamiento farmacológico, y el efecto en las comorbilidades y mortalidad, con el objetivo de comprender de una mejor manera la eficacia, seguridad y costo-efectividad de semaglutida en el tratamiento de pacientes en edad adulta con sobrepeso y obesidad. De acuerdo al análisis crítico la evidencia clínica fue predominantemente de baja certeza según GRADEpro, además de un riesgo de sesgo muy serio. Con respecto a los estudios de evaluación económica, la evidencia mostró que semaglutida 2.4 mg vía SC una vez a la semana como complemento a la LSM, fue más eficaz, segura y costo-efectiva en comparación con liraglutida 3.0 mg más LSM y LSM en la población de participantes con sobrepeso y obesidad sin DM2; de acuerdo a la disponibilidad a pagar que se describe en los estudios.

Metformin monotherapy for adults with type 2 diabetes mellitus.

BACKGROUND: Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified. OBJECTIVES: To assess the effects of metformin monotherapy in adults with T2DM. SEARCH METHODS: We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017). SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument. MAIN RESULTS: We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment. AUTHORS' CONCLUSIONS: There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.

No Acute Effects of Exogenous Glucose-Dependent Insulinotropic Polypeptide on Energy Intake, Appetite, or Energy Expenditure When Added to Treatment With a Long-Acting Glucagon-Like Peptide 1 Receptor Agonist in Men With Type 2 Diabetes.

OBJECTIVE: Dual incretin receptor agonists in clinical development have shown reductions in body weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes, but the impact of glucose-dependent insulinotropic polypeptide (GIP) receptor activation remains unclear. Here, we evaluated the effects of high-dose exogenous GIP on energy intake, energy expenditure, plasma glucose, and glucose-regulating hormones in patients with type 2 diabetes treated with a long-acting glucagon-like peptide 1 receptor (GLP-1R) agonist. RESEARCH DESIGN AND METHODS: In a randomized, double-blind design, men with type 2 diabetes (n = 22, mean ± SEM HbA1c 6.8 ± 0.1% [51 ± 1.5 mmol/mol]) treated with metformin and long-acting GLP-1R agonists were subjected to two 5-h continuous infusions (separated by a washout period of ≥3 days): one with GIP (6 pmol/kg/min) and another with saline (placebo). After 60 min of infusion, a liquid mixed-meal test was performed, and after 270 min of infusion, an ad libitum meal was served for evaluation of energy intake (primary end point). RESULTS: Energy intake was similar during GIP and placebo infusion (648 ± 74 kcal vs. 594 ± 55 kcal, respectively; P = 0.480), as were appetite measures and energy expenditure. Plasma glucagon and glucose were higher during GIP infusion compared with placebo infusion (P = 0.026 and P = 0.017) as assessed by area under the curve. CONCLUSIONS: In patients with type 2 diabetes, GIP infusion on top of treatment with metformin and a long-acting GLP-1R agonist did not affect energy intake, appetite, or energy expenditure but increased plasma glucose compared with placebo. These results indicate no acute beneficial effects of combining GIP and GLP-1.

[Technological Innovations in Diabetes Therapy]. / Technologische Innovationen in der Diabetes-Therapie.

Technological Innovations in Diabetes Therapy Abstract. In the last few years a whole array of technical innovations has dramatically increased treatment options for patients with diabetes mellitus. Capillary blood glucose measurements are increasingly replaced by continuous glucose monitoring. More and more insulin pump systems are linked up to continuous glucose monitoring, which thereby become ever more self-regulating. Novel ultra-long and ultra-short acting insulins have become available. There will soon be oral alternatives for several anti-diabetic treatments, which hitherto needed to be injected.

Safety and efficacy assessment of a GLP-1 mimetic: insulin glargine combination for treatment of feline diabetes mellitus.

A commonly used therapeutic strategy for type 2 diabetes mellitus (DM) in humans involves the use of synthetic incretin hormone-based therapies including exenatide, a glucagon-like pepetide-1 hormone agonist. Glucagon-like pepetide-1 agonists can be used alone or as an ancillary therapy with other agents, including insulin and oral antihyperglycemics. Little is known about the role of these therapies for DM in cats. Therefore, the primary objective of this study was to evaluate the safety and efficacy of short-acting exenatide combined with insulin, as compared to placebo and insulin for the treatment of DM in cats. Treatment with exenatide was well tolerated; only 2 cats developed side effects requiring dose reduction. Two cats (25%) went into diabetic remission while receiving exenatide and insulin, whereas remission was not reported during placebo treatment. The average change in the daily exogenous insulin dose was significant (ß = -0.56 U/kg, 95% confidence interval, -0.96 to -0.15, P = 0.007), and the dose of insulin administered was lower during exenatide treatment. The average weight loss experienced on exenatide was significantly higher than on placebo (ß = 0.65 kg, 95% confidence interval, 0.09-1.21, P = 0.02). There was no significant difference in any of the hormone concentrations evaluated for cats on exenatide vs placebo treatments. Overall, the treatment of diabetic cats with insulin and a fixed dose of exenatide was found to be safe. The weight loss and decreased exogenous insulin requirement experienced with exenatide treatment could be a significant benefit for overweight diabetic cats and warrants further evaluation.

Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. OBJECTIVES: To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence using the GRADE instrument. MAIN RESULTS: We included seven completed RCTs; about 98 participants were randomised to a DPP-4 inhibitor as monotherapy and 1620 participants were randomised to a GLP-1 analogue as monotherapy. Two trials investigated a DPP-4 inhibitor and five trials investigated a GLP-1 analogue. A total of 924 participants with data on allocation to control groups were randomised to a comparator group; 889 participants were randomised to placebo and 33 participants to metformin monotherapy. One RCT of liraglutide contributed 85% of all participants. The duration of the intervention varied from 12 weeks to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported.All-cause and cardiovascular mortality following treatment with GLP-1 analogues were rarely reported; one trial of exenatide reported that no participant died. Another trial of liraglutide 3.0 mg showed that 2/1501 in the liraglutide group versus 2/747 in the placebo group died after 160 weeks of treatment (very low-quality evidence).The incidence of T2DM following treatment with liraglutide 3.0 mg compared to placebo after 160 weeks was 26/1472 (1.8%) participants randomised to liraglutide versus 46/738 (6.2%) participants randomised to placebo (very low-quality evidence). The trial established the risk for (diagnosis of) T2DM as HbA1c 5.7% to 6.4% (6.5% or greater), fasting plasma glucose 5.6 mmol/L or greater to 6.9 mmol/L or less (7.0 mmol/L or greater) or two-hour post-load plasma glucose 7.8 mmol/L or greater to 11.0 mmol/L (11.1 mmol/L). Altogether, 70/1472 (66%) participants regressed from intermediate hyperglycaemia to normoglycaemia compared with 268/738 (36%) participants in the placebo group. The incidence of T2DM after the 12-week off-treatment extension period (i.e. after 172 weeks) showed that five additional participants were diagnosed T2DM in the liraglutide group, compared with one participant in the placebo group. After 12-week treatment cessation, 740/1472 (50%) participants in the liraglutide group compared with 263/738 (36%) participants in the placebo group had normoglycaemia.One trial used exenatide and 2/17 participants randomised to exenatide versus 1/16 participants randomised to placebo developed T2DM (very low-quality evidence). This trial did not provide a definition of T2DM. One trial reported serious adverse events in 230/1524 (15.1%) participants in the liraglutide 3.0 mg arm versus 96/755 (12.7%) participants in the placebo arm (very low quality evidence). There were no serious adverse events in the trial using exenatide. Non-fatal myocardial infarction was reported in 1/1524 participants in the liraglutide arm and in 0/55 participants in the placebo arm at 172 weeks (very low-quality evidence). One trial reported congestive heart failure in 1/1524 participants in the liraglutide arm and in 1/755 participants in the placebo arm (very low-quality evidence). Participants receiving liraglutide compared with placebo had a small mean improvement in the physical component of the 36-item Short Form scale showing a difference of 0.87 points (95% CI 0.17 to 1.58; P = 0.02; 1 trial; 1791 participants; very low-quality evidence). No trial evaluating GLP-1-analogues reported data on stroke, microvascular complications or socioeconomic effects. AUTHORS' CONCLUSIONS: There is no firm evidence that DPP-4 inhibitors or GLP-1 analogues compared mainly with placebo substantially influence the risk of T2DM and especially its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Cost-utility of albiglutide versus insulin lispro, insulin glargine, and sitagliptin for the treatment of type 2 diabetes in the US.

Objective To compare the cost-utility of the glucagon-like peptide-1 receptor agonist albiglutide with those of insulin lispro (both in combination with insulin glargine), insulin glargine, and the dipeptidyl peptidase-4 inhibitor sitagliptin, representing treatments along the type 2 diabetes treatment continuum. Methods The Centre for Outcomes Research and Effectiveness (CORE) Diabetes Model was used for the cost-utility analysis. Data from three Phase 3 clinical trials (HARMONY 6, HARMONY 4, and HARMONY 3) evaluating albiglutide for the treatment of patients with type 2 diabetes were used for the baseline characteristics and treatment effects. Utilities and costs were derived from published sources. Results Albiglutide treatment was associated with an improvement in mean quality-adjusted life expectancy of 0.099, 0.033, and 0.101 years when compared with insulin lispro, insulin glargine, and sitagliptin, respectively. Over the 50-year time horizon, mean total costs in the albiglutide arm were $4332, $2597, and $2223 more than in the other respective treatments. These costs resulted in an incremental cost-utility ratio of $43,541, $79,166, and $22,094 per quality-adjusted life-year (QALY) gained for albiglutide vs insulin lispro, insulin glargine, and sitagliptin, respectively. At a willingness-to-pay threshold of $50,000 per QALY gained, there was a 53.0%, 41.5%, and 67.5% probability of albiglutide being cost-effective compared with the other respective treatments. Limitations This analysis was an extrapolation over a 50-year time horizon based on relatively short-term data obtained during clinical trials. It does not take into account potential differences between the respective treatments in adherence and persistence that can influence both effects and costs. Conclusions Albiglutide represents a reasonable treatment option for patients with type 2 diabetes based on its cost-utility, relative to insulin lispro, insulin glargine, and sitagliptin.

Cost-effectiveness analysis of liraglutide versus sitagliptin or exenatide in patients with inadequately controlled Type 2 diabetes on oral antidiabetic drugs in Greece.

BACKGROUND: To evaluate the long-term cost-effectiveness of liraglutide versus sitagliptin or exenatide, added to oral antidiabetic drug mono- or combination therapy respectively, in patients with Type 2 diabetes in Greece. METHODS: The CORE Diabetes Model, a validated computer simulation model, was adapted to the Greek healthcare setting. Patient and intervention effects data were gathered from a clinical trial comparing liraglutide 1.2 mg once daily vs. sitagliptin 100 mg once daily, both combined with metformin, and a clinical trial comparing liraglutide 1.8 mg once daily vs. exenatide 10 µg twice daily, both as add-on to metformin, glimepiride or both. Direct costs were reported in 2013 Euros and calculated based on published and local sources. All future outcomes were discounted at 3.5% per annum, and the analysis was conducted from the perspective of a third-party payer in Greece. RESULTS: Over a patient's lifetime, treatment with liraglutide 1.2 mg vs. sitagliptin drove a mean increase in discounted life expectancy of 0.13 (SD 0.23) years and in discounted quality-adjusted life expectancy of 0.19 (0.16) quality-adjusted life years (QALYs), whereas therapy with liraglutide 1.8 mg vs. exenatide yielded increases of 0.14 (0.23) years and 0.19 (0.16) QALYs respectively. As regards lifetime direct costs, liraglutide 1.2 mg resulted in greater costs of €2797 (€1468) versus sitagliptin, and so did liraglutide 1.8 mg compared with exenatide (€1302 [€1492]). Liraglutide 1.2 and 1.8 mg doses were associated with incremental cost effectiveness ratios of €15101 and €6818 per QALY gained, respectively. CONCLUSIONS: Liraglutide is likely to be a cost-effective option for the treatment of Type 2 diabetes in a Greek setting.

Cost effectiveness of liraglutide in type II diabetes: a systematic review.

BACKGROUND: As novel treatments for type II diabetes enter the market, there is a need to assess their long-term clinical and economic outcomes against currently available treatment alternatives. Objective compilation and evaluation of current pharmacoeconomic evidence can assist payers and decision makers in determining the appropriate place in therapy of a new medication. OBJECTIVE: Our objective was to review the existing pharmacoeconomic literature evaluating the cost effectiveness and overall costs of treatment associated with liraglutide in type II diabetes. DATA SOURCES: Medical literature indexed in MEDLINE, EMBASE, PsycINFO, CINAHL, and EconLit through 1 June 2014 was searched. STUDY SELECTION: Full-text, English-language cost-effectiveness, cost-utility, and other cost analyses in type II diabetes that compared liraglutide to one or more anti-diabetic agents were included. Initial screening was based on relevance of titles and abstracts followed by examination of the study methods of each remaining manuscript. Studies conducting original pharmacoeconomic analyses were chosen for inclusion. STUDY APPRAISAL METHODS: Articles meeting the inclusion criteria were retrieved, and information on the study design and results was abstracted. Abstracted data elements were chosen and assessed based on the authors' experience as well as criteria set forth by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Health Economic Evaluation Publication Guidelines Task Force. Additionally, reported incremental cost-effectiveness ratios (ICERs) and selected sensitivity analysis results were converted to $US, year 2012 values, in order to facilitate comparison across studies. RESULTS: A total of six cost studies and seven cost-utility studies were identified for inclusion. Across cost studies, liraglutide treatment resulted in costs ranging from a loss of $US2,730 (liraglutide 1.8 mg vs. sitagliptin; pharmacy costs only) over a 1-year time horizon to a savings of $US9,367 (liraglutide 1.8 mg vs. glimepiride; diabetes-related complication costs only) over a 30-year time horizon. Cost-utility analysis results reported base-case ICERs ranging from $US15,774 (vs. glimepiride) to $US40,128 (vs. rosiglitazone) per quality-adjusted life-year (QALY) ($US, year 2012) for liraglutide 1.2 mg and $US8,497 (vs. exenatide) to $US66,031 (vs. rosiglitazone)/QALY ($US, year 2012) for liraglutide 1.8 mg. Estimates were most sensitive to variations in time horizon and cardiovascular complication rates. Based on frequently cited, country-specific cost-utility thresholds, liraglutide was determined to have a probability of being cost effective of between 58 % (liraglutide 1.8 mg vs. sitagliptin) and 93 % (liraglutide 1.2 mg vs. glimepiride). LIMITATIONS: Weaknesses of included studies related primarily to study model inputs that assumed long-term morbidity and mortality benefits in favor of liraglutide based on improvements in clinical biomarkers observed in short-term clinical trials. The exclusion of drug acquisition costs in two identified cost studies as well as the assumed lifetime duration of treatment with liraglutide in several cost-utility studies were also identified as weaknesses. The authors' review was limited by the possibility of incomplete literature retrieval, unintended omission of relevant data elements, and comparison of costs and ICERs generated from healthcare systems from differing countries. CONCLUSIONS: The current literature presents liraglutide as a cost-effective adjunct treatment for type II diabetes that may also be associated with a reduction in diabetes-related complication costs; however, ICER values are largely dependent on assumptions regarding the benefits of long-term liraglutide treatment and the time horizon of the analysis. Real-world use may make liraglutide unattractive from a payer and policy-maker perspective.

Cost-effectiveness of add-on treatments to metformin in a Swedish setting: liraglutide vs sulphonylurea or sitagplitin.

OBJECTIVE: To evaluate long-run cost-effectiveness in a Swedish setting for liraglutide compared with sulphonylureas (glimepiride) or sitagliptin, all as add-on to metformin for patients with type 2 diabetes insufficiently controlled with metformin in monotherapy. METHODS: The IHE Cohort Model of Type 2 Diabetes was used to evaluate clinical and economic outcomes from a societal perspective. Model input data were obtained from two clinical trials, the Swedish National Diabetes Register and the literature. Cost data reflected year 2013 price level. The robustness of results was checked with one-way-sensitivity analysis and probability sensitivity analysis. RESULTS: The cost per QALY gained for liraglutide (1.2 mg) compared to SU (glimepiride 4 mg), both as add-on to metformin, ranged from SEK 226,000 to SEK 255,000 in analyzed patient cohorts. The cost per QALY for liraglutide (1.2 mg) vs sitagliptin (100 mg) as second-line treatment was lower, ranging from SEK 149,000 to SEK 161,000. Costs of preventive treatment were driving costs, but there was also a cost offset from reduced costs of complications of ∼ 20%. Notable cost differences were found for nephropathy, stroke, and heart failure. The predicted life expectancy with liraglutide increased the cost of net consumption for liraglutide. LIMITATIONS: The analysis was an ex-ante analysis using model input data from clinical trials which may not reflect effectiveness in real-world clinical practice in broader patient populations. This limitation was explored in the sensitivity analysis. The lack of specific data on loss of production due to diabetes complications implied that these costs may be under-estimated. CONCLUSIONS: Treatment strategies with liraglutide 1.2 mg improved the expected quality-of-life and increased costs when compared to SU and to sitagliptin for second-line add-on treatments. The cost per QALY for liraglutide was in the range considered medium by Swedish authorities.

Use of antidiabetic drugs in the U.S., 2003-2012.

OBJECTIVE: To describe market trends for antidiabetic drugs, focusing on newly approved drugs, concomitant use of antidiabetic drugs, and effects of safety concerns and access restrictions on thiazolidinedione use. RESEARCH DESIGN AND METHODS: Nationally projected data on antidiabetic prescriptions for adults dispensed from U.S. retail pharmacies were extracted from IMS Health Vector One National and Total Patient Tracker for 2003-2012 and from Encuity Research Treatment Answers and Symphony Health Solutions PHAST Prescription Monthly for 2012. RESULTS: Since 2003, the number of adult antidiabetic drug users increased by 42.9% to 18.8 million in 2012. Metformin use increased by 97.0% to 60.4 million prescriptions dispensed in retail pharmacies in 2012. Among antidiabetic drugs newly approved for marketing between 2003 and 2012, the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin had the largest share with 10.5 million prescriptions in 2012. Rosiglitazone use plummeted to <13,000 prescriptions dispensed in retail or mail-order pharmacies in 2012. Concomitancy analyses showed that 44.9% of metformin use was for monotherapy. Between 33.4 and 48.1% of sulfonylurea, DPP-4 inhibitor, thiazolidinedione, and glucagon-like peptide 1 analog use was not accompanied by metformin. CONCLUSIONS: The antidiabetic drug market is characterized by steady increases in volume, and newly approved drugs experienced substantial uptake, especially DPP-4 inhibitors. The use of rosiglitazone has been negligible since restrictions were put in place in 2011. Further study is needed to understand why one-third to one-half of other noninsulin antidiabetic drug use was not concomitant with metformin use despite guidelines recommending that metformin be continued when other agents are added to treatment.

Real-world cost-effectiveness: lower cost of treating patients to glycemic goal with liraglutide versus exenatide.

INTRODUCTION: While the liraglutide effect and action in diabetes (LEAD-6) clinical trial compared the efficacy and safety of liraglutide once daily (LIRA) to exenatide twice daily (EXEN) in adult patients with type 2 diabetes, few studies have explored the associated per-patient costs of glycemic goal achievement of their use in a real-world clinical setting. METHODS: This retrospective cohort study used integrated medical and pharmacy claims linked with glycated hemoglobin A1C (A1C) results from the IMS Patient-Centric Integrated Data Warehouse. Patients' ≥18 years and naïve to incretin therapies during a 6-month pre-index period, with ≥1 prescription for LIRA or EXEN between January 2010 and December 2010, were included. Patients with evidence of insulin use (pre- or post-index) were excluded. Only patients who were persistent on their index treatment during a 180-day post-index period were included. Follow-up A1C assessments were based on available laboratory data within 45 days before or after the 6-month post-index point in time. Diabetes-related pharmacy costs over the 6-month post-index period were captured and included costs for both the index drugs and concomitant diabetes medications. RESULTS: 234 LIRA and 182 EXEN patients were identified for the analysis. The adjusted predicted diabetes-related pharmacy costs per patient over the 6-month post-index period were higher for LIRA compared to EXEN ($2,002 [95% confidence interval (CI): $1,981, $2,023] vs. $1,799 [95% CI: $1,778, $1,820]; P < 0.001). However, a higher adjusted predicted percentage of patients on LIRA reached A1C < 7% goal (64.4% [95% CI: 63.5, 65.3] vs. 53.6% [95% CI: 52.6, 54.6]; P < 0.05), translating into lower average diabetes-related pharmacy costs per successfully treated patient for LIRA as compared to EXEN ($3,108 vs. $3,354; P < 0.0001). CONCLUSIONS: Although predicted diabetes-related pharmacy costs were greater with LIRA vs. EXEN, a higher proportion of patients on LIRA achieved A1C < 7%, resulting in a lower per-patient cost of A1C goal achievement with LIRA compared to EXEN.

Is treatment with liraglutide efficient?

In the current context of limited economic and health resources, efficiency of drug treatments is of paramount importance, and their clinical effects and related direct costs should therefore be analyzed. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM) which, in addition to its normoglycemic effects, induces a significant improvement in body weight and several cardiovascular risk factors. The aim of this narrative review is to summarize the available evidence about the effects of liraglutide upon cardiovascular risk factors and how these improve its cost-effectiveness profile. Despite the relatively higher cost of liraglutide as compared to other alternative therapies, liraglutide has been shown to be cost-effective when clinical indicators and total costs associated to T2DM management are analyzed.

A prospective, claims-based assessment of the risk of pancreatitis and pancreatic cancer with liraglutide compared to other antidiabetic drugs.

AIM: We evaluated the relationship between liraglutide and acute pancreatitis or pancreatic cancer in an ongoing post-marketing safety assessment programme. METHODS: Initiators of liraglutide, exenatide, metformin, pioglitazone or groups containing initiators of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US commercial health insurance claims database (1 February 2010 to 31 March 2013) and followed for a median of 15 months. We estimated incidence rates (IR/100 000 person-years), rate ratio (RR) and 95% confidence intervals (CI) of new insurance claims with diagnoses of primary inpatient acute pancreatitis or pancreatic cancer from Poisson regression models. RESULTS: The IR for acute pancreatitis for liraglutide was 187.5 compared with 154.4 for all non-glucagon-like peptide-1 (GLP-1)-based therapies (adjusted RR 1.10; CI 0.81-1.49). The IR for pancreatic cancer was 19.9 for liraglutide compared with 33.0 for all non-GLP-1-based therapies (adjusted RR 0.65; 95% CI 0.26-1.60). CONCLUSION: We did not observe excess risk of either outcome associated with liraglutide relative to individual or pooled comparator drugs.

The INITIATOR study: pilot data on real-world clinical and economic outcomes in US patients with type 2 diabetes initiating injectable therapy.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) progression often results in treatment intensification with injectable therapy to maintain glycemic control. Using pilot data from the Initiation of New Injectable Treatment Introduced after Anti-diabetic Therapy with Oral-only Regimens study, real-world treatment patterns among T2DM patients initiating injectable therapy with insulin glargine or liraglutide were assessed. METHODS: This was a retrospective analysis of claims from the OptumInsight™ (OI; January 1, 2010 to July 30, 2010) and HealthCore(®) (HC; January 1, 2010 to June 1, 2010) health insurance databases. Baseline characteristics, health care resource utilization, and costs were compared between adults with T2DM initiating injectable therapy with insulin glargine pen versus liraglutide. Follow-up outcomes, including glycated hemoglobin A1c (A1C), hypoglycemia, health care utilization, and costs, were assessed. RESULTS: At baseline, almost one in three liraglutide patients (OI, n = 363; HC, n = 521) had A1C <7.0%, while insulin glargine patients (OI, n = 498; HC, n = 1,188) had poorer health status, higher A1C (insulin glargine: 9.8% and 9.1% versus liraglutide: 7.9% and 7.7%, OI and HC, respectively, both P < 0.001), and were less likely to be obese (insulin glargine: 10.8% and 9.2% versus liraglutide: 17.4% and 18.8%, OI and HC, respectively, both P < 0.01). The percentage of patients experiencing a hypoglycemic event was numerically higher for insulin pen use for both cohorts (OI 4.4% versus 3.0%; HC 6.2% versus 2.3%). During follow-up, in the insulin glargine cohort, annualized diabetes-related costs remained unchanged ($8,344 versus $7,749 OI, and $7,094 versus $7,731 HC), despite a significant increase in pharmacy costs, due to non-significant decreases in medical costs, while the liraglutide cohort had a significant increase in annualized diabetes-related costs ($4,510 versus $7,731 OI, and $4,136 versus $7,111 HC; both P < 0.001) due to a non-significant increase in medical costs coupled with a significant increase in pharmacy costs. CONCLUSION: These descriptive data identified differences in demographic and baseline clinical characteristics among patients initiating injectable therapies. The different health care utilization and cost patterns warrant further cost-effectiveness analysis.

Retrospective real-world adherence in patients with type 2 diabetes initiating once-daily liraglutide 1.8 mg or twice-daily exenatide 10 µg.

BACKGROUND: The effectiveness of a drug is significantly influenced by a patient's adherence to the required regimen. OBJECTIVE: The goal of this retrospective database analysis was to determine the factors affecting adherence over a 12-month follow-up period in adults with type 2 diabetes mellitus (DM) initiating once-daily liraglutide (1.8 mg) or twice-daily exenatide (10 µg). METHODS: A patient-centric claims database was used, covering the period January 2009 to December 2011. Patients were included if they had ≥1 claim of once-daily liraglutide 1.8 mg or twice-daily exenatide 10 µg from January to December 2010 (index date [ID]), ≥2 diagnoses of type 2 DM before ID, continuous enrollment for 12 months before and after ID, and age ≥18 years at ID. Patients were required to be glucagon-like peptide-1 receptor agonist treatment-naive in the 12 months preceding ID and have a second prescription for once-daily liraglutide 1.8 mg or twice-daily exenatide 10 µg during the 12 months after ID. The medication possession ratio (MPR) was used as a continuous variable and to categorize patients as high-adherent (MPR ≥80%) or low-adherent (MPR <80%). Regression analyses were conducted to determine the predictors for nonadherence in the type 2 DM population, with bivariate testing of the MPR categories conducted initially to determine the predictors to be included in the final regression model. RESULTS: A total of 3623 patients (once-daily liraglutide 1.8 mg, n = 2036; twice-daily exenatide 10 µg, n = 1587) were identified. Variables found to reduce adherence were younger age, female sex, Southern geographic region, twice-daily exenatide treatment, and higher percentage of copayment from the claimant. After adjusting for confounding factors, patients receiving once-daily liraglutide 1.8 mg were ∼11% more adherent than patients receiving twice-daily exenatide 10 µg (95% CI, 7-14; P < 0.0001). The odds ratio for "poor" adherence (MPR <80%) with twice-daily exenatide 10 µg therapy compared with liraglutide 1.8 mg once-daily was 1.33 (95% CI, 1.16-1.53; P < 0.0001). CONCLUSIONS: This study found that adherence to once-daily liraglutide 1.8 mg treatment was superior to twice-daily exenatide 10 µg over a 12-month follow-up period. Nonadherence has important implications to the health care system, both in terms of clinical effectiveness and economic burden (eg, hospitalization, productivity losses). Using strategies to increase adherence is vital to reduce the future clinical and economic burden of diabetes.

Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE).

OBJECTIVE: The epidemic of type 2 diabetes (T2DM) threatens to become the major public health problem of this century. However, a comprehensive comparison of the long-term effects of medications to treat T2DM has not been conducted. GRADE, a pragmatic, unmasked clinical trial, aims to compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes. RESEARCH DESIGN AND METHODS: GRADE was designed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The consensus protocol was approved by NIDDK and the GRADE Research Group. Eligibility criteria for the 5,000 metformin-treated subjects include <5 years' diabetes duration, ≥ 30 years of age at time of diagnosis, and baseline hemoglobin A1c (A1C) of 6.8-8.5% (51-69 mmol/mol). Medications representing four classes (sulfonylureas, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and insulin) will be randomly assigned and added to metformin (minimum-maximum 1,000-2,000 mg/day). The primary metabolic outcome is the time to primary failure defined as an A1C ≥ 7% (53 mmol/mol), subsequently confirmed, over an anticipated mean observation period of 4.8 years (range 4-7 years). Other long-term metabolic outcomes include the need for the addition of basal insulin after a confirmed A1C >7.5% (58 mmol/mol) and, ultimately, the need to implement an intensive basal/bolus insulin regimen. The four drugs will also be compared with respect to selected microvascular complications, cardiovascular disease risk factors, adverse effects, tolerability, quality of life, and cost-effectiveness. CONCLUSIONS: GRADE will compare the long-term effectiveness of major glycemia-lowering medications and provide guidance to clinicians about the most appropriate medications to treat T2DM. GRADE begins recruitment at 37 centers in the U.S. in 2013.

Evaluating the short-term cost-effectiveness of liraglutide versus sitagliptin in patients with type 2 diabetes failing metformin monotherapy in the United States.

BACKGROUND: Effective glycemic control can reduce the risk of serious micro- and macrovascular complications in type 2 diabetes. However, many patients fail to reach glycemic targets due partly to low efficacy and adverse effects of treatment such as hypoglycemia or weight gain. OBJECTIVE: To evaluate the short-term cost-effectiveness of liraglutide versus sitagliptin, in terms of cost per patient reaching a glycated hemoglobin (HbA1c) target with no hypoglycemia and no weight gain after 52 weeks, based on a recently published trial.  METHODS: Data were taken from a 52-week randomized, controlled trial (NCT00700817) in which adults with type 2 diabetes (mean age = 55 years, HbA1c = 8.4%, body mass index = 33 kg/m2) failing metformin monotherapy were randomly allocated to receive either liraglutide 1.2 mg, liraglutide 1.8 mg, or sitagliptin 100 mg daily, in addition to metformin. For the cost-effectiveness analysis, the proportion of patients achieving a clinically relevant composite endpoint, defined as HbA1c less than 7.0%, with no reported hypoglycemia and no gain in body weight, was estimated using logistic regression. Trial data showed that 38.9% of patients on liraglutide 1.2 mg and 49.9% on liraglutide 1.8 mg achieved the composite endpoint, compared with 18.6% on sitagliptin at 52 weeks. Costs of antihyperglycemia medications were accounted for based on published wholesale acquisition costs in 2012 U.S. dollars.  RESULTS: Overall pharmacy costs (needle costs included) were higher for patients on liraglutide than sitagliptin. The cost per patient achieving an HbA1c less than 7% was lowest for patients receiving liraglutide 1.2 mg ($7,993) and highest for patients receiving sitagliptin ($11,570). When expressed as the mean cost per patient reaching target HbA1c with no hypoglycemia or weight gain (cost of control), costs were notably lower on liraglutide than on sitagliptin. Annual mean costs of control were $10,335 on liraglutide 1.2 mg and $11,755 on liraglutide 1.8 mg versus $16,858 on sitagliptin. CONCLUSION: The mean cost per patient achieving control, defined as reaching HbA1c target with no hypoglycemia or weight gain, was lower with liraglutide than with sitagliptin based on data from a recently published 52-week clinical trial.