A short-term economic evaluation of early insulin therapy compared to oral anti-diabetic drugs in order to reduce the major adverse events in type 2 diabetes patients in Iran.

OBJECTIVE: While there are some recommendations about early insulin therapy in newly diagnosed Type 2 Diabetes Mellitus (T2DM) patients, there is not sufficient evidence on this strategy's cost-effectiveness. This study compared early insulin therapy versus oral anti-diabetic drugs (OADs) for managing T2DMusing a cost-effectiveness analysis approach in Iran. METHODS: In this economic evaluation, a decision analytic model was designed. The target population was newly diagnosed type 2 diabetic patients, and the study was carried out from the perspective of Iran's healthcare system with a one-year time horizon. Basal insulin, Dipeptidyl peptidase-4 (DPP-4) inhibitors, and Thiazolidinediones (TZDs) were compared in this evaluation. The main outcome for assessing the effectiveness of each intervention was the reduction in the occurrence of diabetes complications. Strategies were compared using the incremental cost-effectiveness ratio (ICER), and deterministic and probabilistic sensitivity analyses were carried out. RESULTS: The DPP-4 inhibitors strategy was the dominant strategy with the highest effectiveness and the lowest cost. Early insulin therapy was dominated (ICER: $-53,703.18), meaning that it was not cost-effective. The sensitivity analyses consistently affirmed the robustness of the base case findings. The probabilistic sensitivity analysis indicated probabilities of 77%, 22%, and 1% for DPP-4 inhibitors, TZDs strategies, and early insulin therapy, respectively, in terms of being cost-effective. CONCLUSION: In terms of cost-effectiveness, early insulin therapy was not cost-effective compared to OADs for managing newly diagnosed T2DM patients. Future studies in this regard, utilizing more comprehensive evidence, can yield more accurate results.

Cost-Effectiveness of Dipeptidylpeptidase-4 Inhibitors Added to Metformin in Patients With Type 2 Diabetes in China.

Purpose: Dipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context. Materials and Methods: In this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters. Results: Of the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022 versus linagliptin 5 mg, saxagliptin 5 mg, sitagliptin 100 mg and vildagliptin50 mg, respectively. The sitagliptin 100 mg strategy was the cheapest option. The ICER of alogliptin 25 mg against sitagliptin 100 mg strategy was $6,952 per additional QALY gained, and the rest of the strategies were dominated or extended dominated. The most influential parameters were the cost of DPP-4 inhibitors and their treatment efficacy. Conclusions: These results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.

Effects of anti-diabetes medications on cardiovascular and kidney outcomes in Asian patients with type 2 diabetes: a rapid evidence assessment and narrative synthesis.

BACKGROUND: The cardiovascular and kidney safety of glucose-lowering drugs is a key concern in type 2 diabetes (T2D). We evaluated cardiorenal outcomes with glucose-lowering drugs in Asian patients, who comprise over half of T2D cases globally. RESEARCH DESIGN AND METHODS: A rapid evidence assessment was conducted for phase III or IV, double-blind, randomized clinical trials of glucose-lowering drugs reporting cardiovascular or kidney outcomes for Asian T2D patients (Embase, Medline, Cochrane Library databases: 1 January 2008-14 June 2020). RESULTS: Fifty-four publications reported exploratory data for Asians from 18 trials of dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin analogs. SGLT2 inhibitors and several GLP-1 receptor agonists were associated with reduced cardiovascular risk in Asian T2D patients, while DPP-4 inhibitors exhibited cardiovascular safety. SGLT2 inhibitors also appeared to reduce renal risk; however, kidney outcomes were lacking for DPP-4 inhibitors other than linagliptin and GLP-1 receptor agonists in Asian patients. Insulin data were inconclusive as the only trial conducted used different types of insulin as both treatment and comparator. CONCLUSIONS: Cardiorenal outcomes with glucose-lowering drugs in Asian T2D patients were similar to outcomes in the overall multinational cohorts of these trials. DPP-4 inhibitors appear to demonstrate cardiovascular safety in Asians, while SGLT2 inhibitors and some GLP-1 receptor agonists may reduce cardiorenal and cardiovascular risk, respectively.

Prévention d'événements cardiovasculaires et innocuité des inhibiteurs du SGLT2 comparativement aux inhibiteurs de la DPP-4 en contexte réel chez les personnes atteintes de diabète de type 2 / Prevention of cardiovascular events and safety of SGLT2 inhibitors compared to DPP-4 inhibitors in a real-world setting in patients with type 2 diabetes

INTRODUCTION: Les inhibiteurs du cotransporteur sodium-glucose de type 2 (SGLT2) constituent une nouvelle classe d'antidiabétiques oraux. Des essais comparatifs à répartition aléatoire ont indiqué qu'ils réduisaient le risque d'événements cardiovasculaires majeurs (ECM) chez les personnes atteintes de diabète de type 2. Plusieurs avis de sécurité entourant leur utilisation ont été émis, concernant notamment un risque accru d'infection sévère des voies urinaires, d'acidocétose diabétique et d'amputation des membres inférieurs. Toutefois, le risque d'événements cardiovasculaires ainsi que l'innocuité associés à leur utilisation dans un contexte de vie réelle demeurent incertains. MÉTHODOLOGIE: Une étude de cohorte rétrospective multicentrique a été menée à l'aide des bases de données médico-administratives provenant de sept provinces canadiennes et de la base de données cliniques du Clinical Practice Research Datalink du Royaume-Uni. L'utilisation des trois nouvelles classes de médicaments antidiabétiques, soit les inhibiteurs de la dipeptidyl peptidase-4 (DPP-4), les inhibiteurs du SGLT2 et les analogues du glucagon-like peptide-1 (GLP-1), a été décrite pour les nouveaux utilisateurs entre 2016 et 2018. Une approche méthodologique incluant à la fois les nouveaux utilisateurs incidents et les nouveaux utilisateurs prévalents a permis de comparer les inhibiteurs du SGLT2 aux inhibiteurs de la DPP-4 quant au risque d'événements cardiovasculaires ainsi qu'à l'innocuité associés à leur utilisation. Les utilisateurs du SGLT2 ont été appariés à des utilisateurs de DPP-4 sur la base du score de propension le plus proche et selon un niveau comparable de traitement du diabète. Le critère d'évaluation principal était un ECM, défini comme un critère composite de l'infarctus du myocarde, de l'accident vasculaire cérébral ischémique ou d'un décès d'origine cardiovasculaire. Les critères secondaires comprenaient chacun des critères individuels des ECM en plus de la mortalité toutes causes confondues et d'une hospitalisation pour insuffisance cardiaque. Les critères secondaires visant à évaluer l'innocuité étaient l'urosepsie, l'acidocétose diabétique et l'amputation des membres inférieurs. Une cohorte a été créée pour l'ensemble des critères d'évaluation cardiovasculaire ainsi que pour chacun des trois critères d'évaluation portant sur l'innocuité. L'incidence de la gangrène de Fournier a également été évaluée de manière descriptive. Un modèle à risques proportionnels de Cox a été utilisé pour estimer les rapports de risques instantanés (RRI) ajustés et leurs intervalles de confiance (IC) à 95 % comparant l'utilisation des inhibiteurs du SGLT2 à celle des inhibiteurs de la DPP-4 selon une approche dite « telle que traitée dans la réalité ¼. Les analyses ont été réalisées pour chaque critère et dans chacune des régions participantes. Les résultats des sept provinces canadiennes et ceux provenant du Royaume-Uni ont ensuite été regroupés à l'aide d'une méta-analyse utilisant un modèle à effets aléatoires. RÉSULTATS: Entre le 1er janvier 2016 et le 30 juin 2018, un total de 2 175 815 utilisateurs de médicaments antidiabétiques ont été identifiés, dont 166 722 nouveaux utilisateurs d'un inhibiteur du SGLT2 et 194 070 nouveaux utilisateurs d'un inhibiteur de la DPP-4. Parmi les utilisateurs de SGLT2, 36,0 % ont amorcé un traitement avec l'empagliflozine, 33,4 % avec la dapagliflozine et 30,6 % avec la canagliflozine. La proportion de nouveaux utilisateurs de DPP-4 ou de SGLT2 était généralement similaire entre les régions. Certaines variations dans les caractéristiques des nouveaux utilisateurs ont été observées entre les trois classes d'antidiabétiques et entre les régions à l'étude. Au total, 209 867 nouveaux utilisateurs de SGLT2 ont été appariés à 209 867 utilisateurs de DPP-4. Une diminution du risque d'ECM a été observée chez les personnes recevant un inhibiteur du SGLT2 comparativement à celles recevant un inhibiteur de la DPP-4 (RRI : 0,76; IC à 95 % : 0,69-0,84). Une diminution du risque a également été observée pour la mortalité toutes causes confondues (RRI : 0,60; IC à 95 % : 0,54-0,67) et les hospitalisations pour insuffisance cardiaque (RRI : 0,43; IC à 95 % : 0,37-0,51). Des résultats comparables ont été observés pour chacun des critères individuels des ECM. Une diminution du risque d'urosepsie a été observée chez les personnes recevant un inhibiteur du SGLT2 par rapport à celles recevant un inhibiteur de la DPP-4 (RRI : 0,58; IC à 95 % : 0,42-0,80). Le taux d'incidence brut de la gangrène de Fournier était similaire chez les utilisateurs de SGLT2 et de DPP-4 (0,08 contre 0,14 par 1 000 personnesannées). L'utilisation d'un inhibiteur du SGLT2 était également associée à un risque accru d'acidocétose diabétique comparativement à l'utilisation d'un inhibiteur de la DPP-4 (RRI : 2,85; IC à 95 % : 1,99-4,08). Aucune différence n'a cependant été observée pour le risque d'amputation des membres inférieurs entre ces deux classes de médicaments (RRI : 0,88; IC à 95 % : 0,71-1,09). CONCLUSIONS: Dans cette large étude de cohorte rétrospective multicentrique, l'utilisation d'un inhibiteur du SGLT2 est associée à une diminution du risque d'ECM comparativement à l'utilisation d'un inhibiteur de la DPP-4 chez les personnes atteintes de diabète de type 2. Des résultats comparables ont été observés pour les critères individuels des ECM, la mortalité toutes causes confondues et l'insuffisance cardiaque. L'utilisation d'un inhibiteur du SGLT2 est également associée à une diminution du risque d'urosepsie, mais à une augmentation du risque d'acidocétose diabétique. Aucune différence significative n'a été observée entre les utilisateurs de SGLT2 et de DPP-4 concernant l'amputation des membres inférieurs.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral antidiabetics. Randomized controlled trials have shown that they reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes. A number of safety advisories concerning their use have been issued, specifically with regard to an increased risk of severe urinary tract infection, diabetic ketoacidosis and lower extremity amputation. However, the risk of cardiovascular events and the safety associated with the use of these inhibitors in a real-world setting remain uncertain. METHODOLOGY: A multicentre retrospective cohort study was conducted using medical administrative databases from seven Canadian provinces and the UK Clinical Practice Research Datalink clinical database. The use of the three novel classes of antidiabetic drugs, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) agonists, is described for new users between 2016 and 2018. A methodological approach including both incident and prevalent new users was used to compare SGLT2 inhibitors with DPP-4 inhibitors in terms of the risk of cardiovascular events and the safety associated with their use. SGLT2 users were matched to DPP-4 users based on the nearest propensity score and a comparable level of diabetes treatment. The primary endpoint was MACE, defined as a composite of myocardial infarction, ischemic stroke, or cardiovascular death. The secondary endpoints included each of the individual MACE endpoints in addition to all-cause mortality and hospitalization for heart failure. The secondary endpoints for evaluating safety were urosepsis, diabetic ketoacidosis, and lower extremity amputation. A cohort was created for all the cardiovascular endpoints and for each of the three safety endpoints. The incidence of Fournier's gangrene was evaluated descriptively. A Cox proportional risk model was used to estimate the adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs) comparing the use of SGLT2 inhibitors with that of DPP-4 inhibitors using an as-treated approach. Analyses were performed for each endpoint and for each of the participating jurisdictions. The results from the seven Canadian provinces and those from the United Kingdom were then pooled using random-effects meta-analysis. RESULTS: A total of 2,175,815 antidiabetic users were identified for the period from January 1, 2016 to June 30, 2018, including 166,722 new SGLT2 inhibitor users and 194,070 new DPP-4 inhibitor users. Among SGLT2 users, 36.0% initiated treatment with empagliflozin, 33.4% with dapagliflozin and 30.6% with canagliflozin. The proportions of new DPP-4 and new SGLT2 users were generally similar across the jurisdictions. Certain differences in the new users' characteristics were observed between the three classes of antidiabetics na between the jurisdictions involved. In all, 209,867 new SGLT2 users were matched to 209,867 DPP-4 users. A decrease in the risk of MACE was observed in the patients receiving an SGLT2 inhibitor compared with those receiving a DPP-4 inhibitor (HR: 0.76; 95% CI: 0.69-0.84). A decreased risk was also observed for all-cause mortality (HR: 0.60; 95% CI: 0.54-0.67) and hospitalizations for heart failure (HR: 0.43; 95% CI: 0.37- 0.51). Comparable results were obtained for each of the individual MACE endpoints. A decreased risk of urosepsis was observed in patients receiving an SGLT2 inhibitor compared to those receiving a DPP-4 inhibitor (HR: 0.58; 95% CI: 0.42-0.80). The crude incidence rate of Fournier's gangrene was similar in the SGLT2 and DPP-4 users (0.08 versus 0.14 per 1,000 person-years). Additionally, the use of an SGLT2 inhibitor was associated with an increased risk of diabetic ketoacidosis compared to the use of a DPP4 inhibitor (HR: 2.85; 95% CI: 1.99-4.08). However, no difference between these two classes of drugs was observed for the risk of lower extremity amputation (HR: 0.88; 95% CI: 0.71-1.09). CONCLUSIONS: In this large, multicentre retrospective cohort study, the use of an SGLT2 inhibitor was associated with a decreased risk of MACE relative to the use of a DPP-4 inhibitor in patients with type 2 diabetes. Comparable results were observed for the individual MACE endpoints, all-cause mortality, and heart failure. The use of an SGLT2 inhibitor was also associated with a decreased risk of urosepsis but an increased risk of diabetic ketoacidosis. No significant differences were found between the SGLT2 users and DPP-4 users in terms of lower extremity amputations.

Intensification of medical management in type 2 diabetes: A real-world look at primary care practice.

AIMS: To determine which drugs were selected to be added to metformin for patients on dual anti-diabetic medication in the management of type 2 diabetes and to assess HbA1c and BMI outcomes at 6 and 12 months after the initiation of a second anti-diabetic medication. METHODS: A retrospective chart review of electronic medical record data. Second line anti-diabetic medication added to metformin between 7/1/2012 to 8/31/2017 in the primary care practice in Fairview Health System in Minnesota. RESULTS: 3413 patients met the selection criteria of type 2 diabetes, 18 years and older, dual anti-diabetes therapy with metformin being the first prescribed. The most frequently prescribed medications added to metformin were sulfonylurea and basal insulin accounting for 51% (1724/3413) and 37% (1268/3413) respectively. Mean HbA1c reductions at 6 and 12 months among 2134 patients with baseline and follow-up HbA1c data respectively were: GLP-1 agonist (-1.3, P < 0.001; -1.2, P < 0.001), sulfonylurea (-1.1, P < 0.001; -0.9, P < 0.001), basal insulin (-1.1, P < 0.001; -1.0, P < 0.001), DPP4 inhibitor (-0.7, P = 0.223; -0.8, P = 0.049). Patients prescribed a GLP-1 agonist had a higher mean baseline BMI (BMI =40.3 kg/m2) and this was the only group with a statistically significant BMI reduction from baseline at 6 and 12 months (-1.5, P = 0.049 and -1.8, P = 0.041). CONCLUSION AND RELEVANCE: Type 2 diabetes patients treated with sulfonylurea, basal insulin and GLP-1 agonist as an add on to metformin had significant reductions in HbA1c. Patients prescribed a GLP-1 agonist had a significant BMI reduction.

Penetration of new antidiabetic medications in East Asian countries and the United States: A cross-national comparative study.

BACKGROUND: The number of patients with diabetes is increasing particularly in Asia-Pacific region. Many of them are treated with antidiabetics. As the basis of the studies on the benefit and harm of antidiabetic drugs in the region, the information on patterns of market penetration of new classes of antidiabetic medications is important in providing context for subsequent research and analyzing and interpreting results. METHODS: We compared penetration patterns of dipeptidyl peptidase-4 (DPP-4) inhibitors in Taiwan, Hong Kong, Japan, and the United States. We used the Taiwan National Health Insurance Research Database, a random sample of the Hong Kong Clinical Data Analysis and Reporting System, the Japan Medical Data Center database, and a 5% random sample of the US Medicare database converted to the Observational Medical Outcomes Partnership's Common Data Model to identify new users of oral antidiabetic medications. We standardized prevalence and incidence rates of medication use by age and sex to those in the 2010 Taiwanese population. We compared age, sex, comorbid conditions, and concurrent medications between new users of DPP-4 inhibitors and biguanides. RESULTS: Use of DPP-4 inhibitors 1 year after market entry was highest in Japan and lowest in Hong Kong. New users had more heart failure, hyperlipidemia, and renal failure than biguanide users in Taiwan, Hong Kong, and the United States while the proportions were similar in Japan. In a country with low penetration of DPP-4 inhibitors (eg, Hong Kong), users had diabetes with multiple comorbid conditions compared with biguanidine users. In a country with high penetration (eg, Japan), the proportion of users with comorbid conditions was similar to that of biguanide users. CONCLUSIONS: We observed a marked difference of the penetration patterns of newly marketed antidiabetics in different countries in Asia. Those results will provide the basic information useful in the future studies.

Concordance with prescribing information dosage recommendations for dipeptidyl-peptidase-4 inhibitors among type 2 diabetes mellitus patients with moderate to severe chronic kidney disease.

OBJECTIVE: To estimate the proportion of patients with moderate to severe chronic kidney disease (CKD) whose initial dipeptidyl-peptidase-4 inhibitor (DPP4-i) dosage was concordant with prescribing information (label) recommendations in the United States. METHODS: Adult patients with type 2 diabetes mellitus (T2DM) who initiated a DPP4-i (linagliptin, sitagliptin, saxagliptin) between 1 January 2011 and 30 June 2014 were identified using electronic medical records and administrative claims, with index date being the date of first observed DPP4-i treatment. Patients were required to have chronic kidney disease (CKD) stage 3b, 4 or 5 (estimated Glomerular Filtration Rate [eGFR] value <45 ml/min/1.73 m2) during the 12 month pre-index period. Patients were classified as concordant or not concordant based on whether the first prescribed dose was consistent with label recommendations. Demographics, clinical characteristics, resource use and costs during pre-index were evaluated by DPP4-i concordance status. RESULTS: Of the 492 patients (323 sitagliptin, 57 saxagliptin, 112 linagliptin), 36.2% were prescribed doses that were not concordant with label recommendations (44.9% for sitagliptin, 57.9% for saxagliptin and 0% for linagliptin [which does not require dosage adjustment]). Concordant patients were slightly older (mean age 71 years vs. 68, p = .01) but had similar gender distribution (55% vs. 60% female, p = .31) compared to those who were not concordant. They had lower general health status (Charlson Comorbidity Score 2.6 vs. 2.2, p = .03), and had similar pre-index all-cause total costs ($25,245 vs. $21,972, p = .68) and lower pre-index T2DM-related costs ($1618 vs. $1922, p = .05). CONCLUSIONS: More than a third of DPP4-i patients with CKD stage 3b or higher were prescribed doses not concordant with DPP4-i label dosage recommendations.

Geographical variation in anti-diabetic prescribing in Ireland in 2013 and 2014: a cross-sectional analysis.

Background: Several new medications for type 2 diabetes (T2DM) have been introduced, including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor (GLP-1) agonists. Variation in the prescribing of these agents has implications for quality, safety and costs. We aimed to investigate geographical variation in the prescribing of anti-diabetic medications in Ireland. Methods: Cross-sectional analyses were undertaken on the two main national pharmacy claims databases in Ireland in 2013 and 2014. Direct standardized rates of individual anti-diabetic medication prescribing per 100 000 population were calculated by geographical area. Variation in prescribing was assessed using the systematic component of variation (SCV) and classified as very high (>10), high (5.4-10), moderate (3-5.4) or low (<3). Estimated total costs of prescribing were calculated per geographical area using medication wholesale costs. Results: Very high levels of geographical variation of GLP-1 agonists (SCV 11.4 and 10.3 in 2013 and 2014) and moderate variation of DPP-4 inhibitors (SCV 3.8 and 4.1) were found. There was low/moderate variation in the prescribing of sulphonylureas (SVC 2.8 and 3.6) and low variation in prescribing of metformin (SVC 1.7 and 2.0). Geographical variation in Ireland leads to an estimated total wholesale cost differential of €500 000 for GLP-1 agonists, per 100 000 population, between the highest and lowest prescribing areas. Conclusions: There is substantial geographical variation in the prescribing of new T2DM medicines, particularly GLP-1 agonists. The prescribing variation which was identified may not only represent differences in the application of clinical guidelines, but also variation in professional opinion or patient preference.

Comparative adherence to diabetes drugs: An analysis of electronic health records and claims data.

Non-adherence to medications is a major challenge in diabetes care. The objective of this brief report is to compare adherence rates for 6 major classes of diabetes medications: metformin, sulfonylurea, thiazolidinedione, basal insulin, DPP-4 inhibitors, and GLP-1 receptor agonists. We used a data source that linked electronic prescriptions with insurance claims to assess whether new electronic prescriptions for diabetes medications were followed by dispensing claims consistent with that prescription. After one year of follow-up, the daily medication possession probability (MPP) - a measure of overall adherence - at one year for sulfonylurea was 0.49 and for metformin was 0.46. Thiazolidinediones and basal insulin had a similar final daily MPP at 0.36 and 0.39, respectively, which was significantly lower than that for sulfonylurea or metformin (P < .05). GLP-1 receptor agonists and DPP-4 inhibitors were also comparable to one another at a final daily MPP of .30 and .21, respectively (P < .05 compared to any of the aforementioned drug classes). In summary, the rates at which diabetes drugs are prescribed, and the rates at which patients actually take them, differ substantially. Physicians should be aware of potentially significant challenges concerning adherence to newer agents.

Cost-effectiveness of dipeptidyl peptidase-4 inhibitor monotherapy versus sulfonylurea monotherapy for people with type 2 diabetes and chronic kidney disease in Thailand.

OBJECTIVE: With a high prevalence of chronic kidney disease (CKD) in type 2 diabetes (T2DM) in Thailand, the appropriate treatment for the patients has become a major concern. This study aimed to evaluate long-term cost-effective of dipeptidyl peptidase-4 (DPP-4) inhibitor monothearpy vs sulfonylurea (SFU) monotherapy in people with T2DM and CKD. METHODS: A validated IMS CORE Diabetes Model was used to estimate the long-term costs and outcomes. The efficacy parameters were identified and synthesized using a systematic review and meta-analysis. Baseline characteristics and cost parameters were obtained from published studies and hospital databases in Thailand. Costs were expressed in 2014 US Dollars. Outcomes were presented as an incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to estimate parameter uncertainty. RESULTS: From a societal perspective, treatment with DPP-4 inhibitors yielded more quality-adjusted life years (QALYs) (0.024) at a higher cost (>66,000 Thai baht (THB) or >1,829.27 USD) per person than SFU, resulting in the ICER of >2.7 million THB/QALY (>74,833.70 USD/QALY). The cost-effectiveness results were mainly driven by differences in HbA1c reduction, hypoglycemic events, and drug acquisition cost of DPP-4 inhibitors. At the ceiling ratio of 160,000 THB/QALY (4,434.59 USD/QALY), the probability that DPP-4 inhibitors are cost-effective compared to SFU was less than 10%. CONCLUSIONS: Compared to SFU, DPP-4 inhibitor monotherapy is not a cost-effective treatment for people with T2DM and CKD in Thailand.

Adherence to dipeptidyl peptidase-4 inhibitor therapy among type 2 diabetes patients with employer-sponsored health insurance in Japan.

AIMS/INTRODUCTION: Dipeptidyl peptidase-4 inhibitors (DPP-4i) are a common first-line treatment for type 2 diabetes in Japan. However, little is known about patients' medication adherence, persistence and discontinuation in this setting. MATERIALS AND METHODS: This was a retrospective cohort study of new DPP-4i users in a Japanese claims database. Adult patients (age 18-65 years) with type 2 diabetes diagnosis and no diagnosis of other diabetes or pregnancy during the study period were included if they were prescribed a DPP-4i as monotherapy or combination oral therapy. Adherence to therapy was measured using the proportion of days covered method over a fixed period of 1 year. The proportion of days covered of ≥80% was considered adherent. Persistence was defined as continuing index DPP-4i treatment with <90-day gap between refills. Patient baseline characteristics were explored as potential predictors of DPP-4i discontinuation and adherence in multivariable models. RESULTS: The final sample contained 2,874 monotherapy and 3,016 dual therapy patients. The mean age was approximately 51 years, and 75% were men. The mean proportion of days covered was 76.6% among monotherapy patients and 82.5% among dual therapy patients, with 67.2% of monotherapy and 74.4% of dual therapy patients classified as adherent. At 12 months, 72.2% of monotherapy and 79.2% of dual therapy patients were persistent. In adjusted models, younger age and having fewer concomitant medications were significantly associated with lower adherence and higher discontinuation, in both treatment groups. CONCLUSIONS: Those under the age of 45 years, and those with fewer concomitant medications were less likely to be adherent and persistent, and more likely to discontinue DPP-4i therapy.

Severe hypoglycaemia in adults with insulin-treated diabetes: impact on healthcare resources.

AIMS: To assess resource utilization associated with severe hypoglycaemia across three insulin regimens in a large phase 3a clinical programme involving people with Type 1 diabetes treated with basal-bolus insulin, people with Type 2 diabetes treated with multiple daily injections and people with Type 2 diabetes treated with basal-oral therapy. METHODS: Data relating to severe hypoglycaemia events (defined as episodes requiring external assistance) from the insulin degludec and insulin degludec/insulin aspart programme (15 trials) were analysed using descriptive statistics. Comparators included insulin glargine, biphasic insulin aspart, insulin detemir and sitagliptin. Mealtime insulin aspart was used in some regimens. This analysis used the serious adverse events records, which documented the use of ambulance/emergency teams, a hospital/emergency room visit ≤ 24 h, or a hospital visit > 24 h. RESULTS: In total, 536 severe hypoglycaemia events were analysed, of which 157 (29.3%) involved an ambulance/emergency team, 64 (11.9%) led to hospital/emergency room attendance of ≤ 24 h and 36 (6.7%) required hospital admission (> 24 h). Although there were fewer events in people with Type 2 diabetes compared with Type 1 diabetes, once a severe episode occurred, the tendency to utilize healthcare resources was higher in Type 2 diabetes vs. Type 1 diabetes. A higher proportion (47.6%) in the basal-oral therapy group required hospital treatment for > 24 h versus the Type 1 diabetes (5.0%) and Type 2 diabetes multiple daily injections (5.3%) groups. CONCLUSION: This analysis suggests that severe hypoglycaemia events often result in emergency/ambulance calls and hospital treatment, incurring a substantial health economic burden, and were associated with all insulin regimens.

Short-term dipeptidyl peptidase-4 inhibitor use increases the risk of herpes zoster infection in Asian patients with diabetes.

BACKGROUND: We aimed to evaluate whether patients with diabetes who use dipeptidyl peptidase (DPP)-4 inhibitors are at a higher risk of developing a herpes zoster (HZ) infection. METHODS: We used a subset of the Longitudinal Health Insurance Database 2000 containing all inpatient and outpatient medical claims of ∼1 million people who were randomly sampled from the National Health Insurance Research Database. Patients who were newly diagnosed with Type 2 diabetes International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM 250.x0 and 250.x2) who used antidiabetic medications were divided into two cohorts based on their use of DPP-4 inhibitors between 2009 and 2011. Cox proportion hazard regression models were used to assess the effects of DPP-4 inhibitors on the incidence of HZ compared with the non-DPP-4-inhibitor-exposed cohort. RESULTS: Patients in DPP-4-inhibitor-exposed cohort with diabetes and HZ infections revealed an incidence density of 4.20 per 1000 person-years compared with 3.50 per 1000 person-years for the non-DPP-4-inhibitor-exposed cohort (adjusted hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.70-1.99). Furthermore, high-dose DPP-4-inhibitor treatment was associated with a significantly higher risk of HZ (adjusted HR = 2.46, 95% CI = 1.16-5.19 for a defined daily dose [DDD] ≥ 360). In addition, short-term DPP-4-inhibitor treatment was associated with a significantly higher risk of HZ (adjusted HR = 2.04, 95% CI = 1.03-4.04 for a DDD ≥ 360 days). CONCLUSION: These results suggest that Asian patients with diabetes who use short-term DPP-4 inhibitors might be at a higher risk of developing HZ.

[Once-weekly DPP-4 inhibitor].

Trelagliptin is the first once-weekly dipeptidyl peptidase-4(DPP-4) inhibitor in the world. Trelagliptin inhibits DPP-4 activity with lower drug concentration compared with other once- (or twice-) daily DPP-4 inhibitors in in vitro study. More than 70 % of DPP-4 activity is inhibited even 1 week after administration of trelagliptin administration in human study. 24-week trelagliptin monotherapy improved HbA1c(-0.33%) and fasting plasma glucose levels in Japanese patients with type 2 diabetes. Trelagliptin did not affect body weight and frequency of hypoglycemic events in this study. 52-week monotherapy and add-on therapy of trelagliptin also improved HbA1c levels without body weight gain and severe hypoglycemia. Therefore, trelagliptin has high efficacy and safety on glucose control in Japanese patients with type 2 diabetes.

Cost effectiveness of dipeptidyl peptidase-4 inhibitors for type 2 diabetes.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs used for treating type 2 diabetes mellitus. While many studies have reported on the cost-effectiveness of DPP-4 inhibitors for treating type 2 diabetes, a systematic review of economic evaluations of DPP-4 inhibitors is currently lacking. OBJECTIVES: The aim of this systematic review was to assess the cost effectiveness of DPP-4 inhibitors for patients with type 2 diabetes. DATA SOURCES: MEDLINE, EMBASE, National Health Service Economic Evaluation Database (NHS EED), Web of Science, EconLit databases, and the Cochrane Library were searched in November 2013. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Studies assessing the cost effectiveness of DPP-4 inhibitors for type 2 diabetes were eligible for analysis. DPP-4 inhibitor monotherapy or combinations with other antidiabetic agents were included in the review. The DPP-4 inhibitors were all marketed drugs. Two reviewers independently reviewed titles, abstracts, and articles sequentially to select studies for data abstraction based on the inclusion and exclusion criteria. Disagreements were resolved by consensus. STUDY APPRAISAL AND SYNTHESIS METHODS: The quality of included studies was assessed according to the 24-item checklist of the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. The costs reported by the included studies were converted to US dollars via purchasing power parities (PPP) in the year 2013 using the CCEMG-EPPI-Center Cost Converter. RESULTS: A total of 11 published studies were selected for inclusion; all were cost-utility analyses. Nine studies were conducted from a payer perspective and one used a societal perspective; however, the perspective of the other study was unclear. Four studies were of good quality, six were of moderate quality, and one was of low quality. Of the seven studies comparing DPP-4 inhibitors plus metformin with sulfonylureas plus metformin, six concluded that DPP-4 inhibitors were cost effective in patients with type 2 diabetes who were no longer adequately controlled by metformin monotherapy. Five studies compared DPP-4 inhibitors with thiazolidinediones, and whether DPP-4 inhibitors were cost effective was uncertain. Only two economic evaluations provided data to compare DPP-4 inhibitors versus insulin, and the results favored the use of DPP-4 inhibitors as second-line therapy. LIMITATIONS: Synthesis of the data was impossible because of heterogeneity in the methodology and data sources of the economic evaluations, and the inclusion criteria excluded conference abstracts. It was difficult to find reliable weightings for each of the items of the CHEERS checklist, and the ratings were dichotomous. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This study provides the first systematic evaluation of DPP-4 inhibitors for patients with type 2 diabetes. It found that, in patients with type 2 diabetes who do not achieve glycemic targets with antidiabetic monotherapy, DPP-4 inhibitors as add-on treatment may represent a cost-effective option compared with sulfonylureas and insulin. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.

A fixed-dose combination tablet of gemigliptin and metformin sustained release has comparable pharmacodynamic, pharmacokinetic, and tolerability profiles to separate tablets in healthy subjects.

BACKGROUND: In type 2 diabetes mellitus, fixed-dose combination (FDC) can provide the complementary benefits of correction of multiple pathophysiologic defects such as dysfunctions in glycemic or metabolic control while improving compliance compared with separate tablets taken together. The objective of the study reported here was to compare the pharmacodynamic (PD), pharmacokinetic (PK), and tolerability profiles of gemigliptin and extended-release metformin (metformin XR) between FDC and separate tablets. METHODS: A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 28 healthy male volunteers. Two FDC tablets of gemigliptin/metformin 25/500 mg or separate tablets of gemigliptin (50 mg ×1) and metformin XR (500 mg ×2) were orally administered in each period. Serial blood samples were collected up to 48 hours post-dose to determine dipeptidyl peptidase 4 (DPP-4) activity using spectrophotometric assay and concentrations of gemigliptin and metformin using tandem mass spectrometry. Geometric mean ratios (GMRs) of FDC to separate tablet formulations and their 90% confidence intervals (CIs) were calculated to compare the PD and PK parameters between the two formulations. Tolerability was assessed throughout the study. RESULTS: The plasma DPP-4 activity-time curves of the FDC and the separate tablets almost overlapped, leading to a GMR (90% CI) of the FDC to separate tablets for the plasma DPP-4 activity and its maximum inhibition of 1.00 (0.97-1.04) and 0.92 (0.82-1.05), respectively. Likewise, all of the GMRs (90% CIs) of FDC to separate tablets for the area under the plasma concentration-time curve and maximum plasma concentration of gemigliptin and metformin fell entirely within the conventional bioequivalence range of 0.80-1.25. Both the FDC and separate tablets were well tolerated. CONCLUSION: The PD, PK, and tolerability profiles of gemigliptin and metformin XR in FDC and separate tablets were found to be comparable. The FDC tablet of gemigliptin and metformin sustained release can be a convenient therapeutic option in patients with type 2 diabetes mellitus requiring a combination approach.

Use of the Japanese health insurance claims database to assess the risk of acute pancreatitis in patients with diabetes: comparison of DPP-4 inhibitors with other oral antidiabetic drugs.

This study was initiated to evaluate the association of acute pancreatitis (AP) with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with diabetes in Japan. A retrospective cohort study of a large medical and pharmacy claims database was performed to compare the incidence of AP among those receiving DPP-4 inhibitors and those receiving other oral antidiabetic drugs. The incidence of all AP and hospitalizations for AP was similar between the two groups. Previous exposure to DPP-4 inhibitors did not affect occurrence of AP in patients on other oral antidiabetic drugs. The Kaplan-Meier curve for time to AP was similar between the two groups, and was not affected by previous exposure to DPP-4 inhibitors. The Cox proportional hazard models showed the incidence of AP was not significantly higher in those receiving DPP-4 inhibitors. Despite numerous, important limitations related to claims database-based analyses, our results indicate that there is no increased risk of AP with use of DPP-4 inhibitors among patients with diabetes in Japan.

Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study.

AIM: To compare pancreatic cancer incidence and diagnostic evaluation among patients initiating dipeptidyl-peptidase-4 (DPP-4) inhibitor treatment with those initiating sulfonylureas (SU) and thiazolidinediones (TZD). METHODS: Medicare claims data were examined in a new-user active-comparator cohort study. Patients >65 years with no prescriptions for DPP-4 inhibitors, SU or TZD at baseline were included if they had at least two claims for the same drug within 180 days. Using an as-treated approach and propensity score-adjusted Cox models, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer. Diagnostic evaluations were compared using risk ratios. RESULTS: In the DPP-4 inhibitor versus SU comparison, there were 18 179 patients who initiated treatment with DPP-4 inhibitors, of whom 26 developed pancreatic cancer (interquartile range follow-up 5-18 months). In the DPP-4 inhibitor versus TZD comparison there were 29 366 people initiating DPP-4 inhibitor treatment and 52 of these developed pancreatic cancer. The risk of pancreatic cancer with DPP-4 inhibitor treatment was lower relative to SU treatment (HR: 0.6, CI: 0.4-0.9) and similar to TZD treatment (HR: 1.0, 95% CI: 0.7-1.4). After the first 6 months of follow-up were excluded to reduce the potential for reverse causality, the results were not altered. The probability of diagnostic evaluation after commencing DPP-4 inhibitor treatment (79.3%) was similar to that for TZD (74.1%, risk ratio 1.06, 95% CI: 1.05-1.07) and SU (74.6%) (risk ratio 1.06, 95% CI: 1.05-1.07). The probability of diagnostic evaluation before the index date (date of initiating treatment) was ∼80% for all cohorts. CONCLUSION: Although the present study was limited by sample size and the observed duration of treatment in the USA, our well-controlled population-based study suggests there is no higher short-term pancreatic cancer risk with DPP-4 inhibitor treatment relative to SU or TZD treatment.

Healthcare costs of the combination of metformin/dipeptidyl peptidase-4 inhibitors compared with metformin/other oral antidiabetes agents in patients with type 2 diabetes and metabolic syndrome.

OBJECTIVES: This study assessed the health costs resulting from the combination of metformin/dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin/oral antidiabetes drugs in patients with type 2 diabetes and metabolic syndrome (MS). PATIENTS AND METHODS: An observational retrospective study was performed. Patients ≥30 years of age who were receiving treatment with metformin who started a second oral antidiabetes therapy in 2008 and 2009 were included. Patients were divided into two groups: (a) metformin plus DPP-4 inhibitors and (b) metformin plus other oral antidiabetes drugs. The main measures were compliance, persistence, metabolic control (glycosylated hemoglobin level of <7%), and complications (hypoglycemia and cardiovascular events). Healthcare and non-healthcare costs were calculated. Patients were followed up for 2 years. An analysis of covariance was carried out (P<0.05 was considered significant). RESULTS: Of the 1,435 patients (mean age, 67.3 years; 53.1% male) who were enrolled, 442 (30.8%) were receiving metformin plus DPP-4 inhibitors, and 993 (69.2%) were receiving metformin plus other oral antidiabetes drugs. The prevalence of MS was 72.2% (95% confidence interval, 71.1-73.3%). Patients treated with DPP-4 inhibitors had better compliance (69.1% vs. 63.8%), persistence (63.8% vs. 53.1%), and metabolic control (69.9% vs. 64.3%) (P<0.01) compared with those receiving other antidiabetes drugs, lower rates of hypoglycemia (14.3% vs. 41.1%) and cardiovascular events (2.9% vs. 5.7%) (P<0.01), and a lower mean adjusted unit cost (€2,278 vs. €2,631; P=0.003). CONCLUSIONS: Despite the limitations of this observational study, diabetes patients with MS who were treated with metformin plus DPP-4 inhibitors had better compliance, greater metabolic control, and lower rates of hypoglycemia, causing lower costs for the Spanish national health system than patients receiving metformin plus other antidiabetes drugs.

Cost-effectiveness of metformin plus vildagliptin compared with metformin plus sulphonylurea for the treatment of patients with type 2 diabetes mellitus: a Portuguese healthcare system perspective.

OBJECTIVE: To evaluate the cost-effectiveness of vildagliptin plus metformin vs generic sulphonylurea plus metformin in patients with type 2 diabetes mellitus, not controlled with metformin, from a Portuguese healthcare system perspective. METHODS: A cost-effectiveness model was constructed using risk equations from the UK Prospective Diabetes Study Outcomes Model with a 10,000-patient cohort and a lifetime horizon. The model predicted microvascular and macrovascular complications and mortality in yearly cycles. Patients entered the model as metformin monotherapy failures and switched to alternative treatments (metformin plus basal-bolus insulin and subsequently metformin plus intensive insulin) when glycated hemoglobin A1c >7.5% was reached. Baseline patient characteristics and clinical variables were derived from a Portuguese epidemiological study. Cost estimates were based on direct medical costs only. One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. RESULTS: There were fewer non-fatal diabetes-related adverse events (AEs) in patients treated with metformin plus vildagliptin compared with patients treated with metformin plus sulphonylurea (6752 vs 6815). Addition of vildagliptin compared with sulphonylurea led to increased drug acquisition costs but reduced costs of AEs, managing morbidities, and monitoring patients. Treatment with metformin plus vildagliptin yielded a mean per-patient gain of 0.1279 quality-adjusted life years (QALYs) and a mean per-patient increase in total cost of €1161, giving an incremental cost-effectiveness ratio (ICER) of €9072 per QALY. Univariate analyses showed that ICER values were robust and ranged from €4195 to €16,052 per QALY when different parameters were varied. LIMITATIONS: The model excluded several diabetes-related morbidities, such as peripheral neuropathy and ulceration, and did not model second events. Patients were presumed to enter the model with no diabetes-related complications. CONCLUSION: Treatment with metformin plus vildagliptin compared with metformin plus sulphonylurea is expected to result in a lower incidence of diabetes-related AEs and to be a cost-effective treatment strategy.