Healthcare Resource Utilization and Associated Costs in New Users of Empagliflozin versus DPP-4 Inhibitors and GLP-1 Agonists: A Comparative Analysis Based on Retrospective Real-World Data from German Sickness Funds.

Purpose: Achieving good glycemic control in type 2 diabetes (T2DM) may require individualized pharmacological approaches. We aimed to compare direct healthcare costs in patients treated with empagliflozin (EMPA) compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1-RA). Patients and Methods: This German claims data study included continuously insured persons with at least two outpatient diagnoses and/or one inpatient diagnosis of T2DM if they started EMPA, DPP-4i, or GLP-1-RA in 2015-2018. Healthcare costs were assessed from therapy initiation until the end of data availability, death, or therapy discontinuation and compared among propensity score-matched cohorts. Results: Of 24,465 patients included, 3285 received EMPA, 19,443 DPP-4i, and 1747 GLP-1-RA. Matched cohorts were balanced on baseline characteristics (EMPA versus DPP-4i: n1/n2 = 3100/3100 and EMPA versus GLP-1-RA: n3/n4 = 1346/1346). Mean total costs after start of DPP-4i were €7009 (95%-CI: 6573-7444) versus €4274 (3982-4566) for EMPA. Costs associated with GLP-1-RA treatment were also significantly higher compared with EMPA (€6851 [6183-7518] versus €4895 [4345-5445]). Conclusion: Although the individual clinical patient profile and physician assessment are paramount in treatment decisions, substantial differences in the economic impact of different antidiabetic therapies should be considered.

Guideline Adherence and Associated Outcomes in the Treatment of Type 2 Diabetes Mellitus Patients With an Incident Cardiovascular Comorbidity: An Analysis Based on a Large German Claims Dataset.

INTRODUCTION: According to current guidelines, appropriate drug treatment is the backbone of the effective management of cardiovascular (CV) comorbidities in patients with type 2 diabetes mellitus (T2DM). The main objective of this study was to assess the degree of real-world adherence to these guideline recommendations and to identify whether poor guideline adherence is associated with worse clinical outcomes. METHODS: In this retrospective German claims data analysis (AOK PLUS dataset), patients with T2DM with an incident diagnosis (index date) of ischemic stroke, myocardial infarction, heart failure or coronary artery disease were observed for 12 months between 1 January 2014 and 31 December 2017. We assessed guideline adherence per observed CV disease combination at three levels: "green" if patients received prescriptions of all recommended medications with > 185 defined daily doses (DDDs) per observed patient-year; "yellow" if patients received at least two prescriptions of at least one of the recommended medications; and "red" if patients did not receive at least two prescriptions of at least one of the recommended medications. The impact of the assignment of a patient to one of these three levels on all-cause mortality and CV risk was analyzed based on multivariable Cox regression analyses and reported as adjusted hazard ratios (HRs). RESULTS: We identified 32,916 patients with T2DM with an incident CV comorbidity (mean age 75.0 years, 54.2% female, Charlson Comorbidity Index [CCI]: 5.5). Observed patients received at least 185 DDDs of the following medication classes in the 12 months before/after the index date: vitamin K antagonists (6%/6%); antiplatelet drugs (9%/27%); novel oral anticoagulants (3%/13%); diuretics (48%/54%); beta blockers (31%/35%); calcium-channel blockers (34%/32%); renin-angiotensin-aldosterone system inhibitors (69%/68%); and lipid-modifying agents (19%/37%). When post-index therapy was compared to guideline recommendations, the level of "guideline adherence" was classified as "green" for 14.4% of the patients, "yellow" for 75.2% and "red" for 10.5%. An assignment of "red" was associated with worse CV outcomes in all analyses. Regarding mortality, in addition to one additional year of age (hazard ratio [HR] 1.04), CCI (HR 1.17), use of insulins (HR 1.25), digitalis glycosides (HR 1.52) and diuretics (HR 1.32), non-adherence to guideline recommendations ("red": HR 6.79; "yellow": HR: 1.30) was a significant predictor for early death, while female gender (HR 0.79), the participation in a disease management program (HR 0.69) and the use of antidiabetics other than insulin (HR 0.74) were generally associated with a reduced risk. CONCLUSION: Only a minority of patients with T2DM and an incident CV comorbidity receive a treatment fully adherent with guideline recommendations. This may contribute to high mortality rates in this population in clinical practice.

Real-world clinical outcomes and costs in type 2 diabetes mellitus patients after initiation of insulin therapy: A German claims data analysis.

BACKGROUND: This study describes real-world treatment-related outcomes and healthcare costs of German type 2 diabetes mellitus (T2D) patients who initiated insulin therapy. METHODS: This retrospective analysis includes German claims data from 01/01/2012 until 31/12/2016. Identification of eligible patients took place between 01/01/2013 and 31/12/2015, allowing for at least 1 year of follow-up. Clinical outcomes, such as HbA1c values and body mass index, were observed in a subpopulation participating in a Disease Management Program. Healthcare expenditures were evaluated for the first year of therapy. RESULTS: Overall, 27,340 insulin starters with T2D were observed (mean age: 72.2 years, female: 51.4%). Treatment-related outcomes were evaluated in a subsample of 12,034 patients. Patients who started insulin combined with other antidiabetic drugs (ADs) achieved their HbA1c goals more frequently than patients on insulin monotherapy (+10.7 percentage points [pp] vs. +21.1 pp for insulin plus metformin). All-cause costs were by far highest among patients with insulin monotherapy (€ 12,283 per patient-year) compared with patients receiving a combined AD regimen (€ 9,947-10,509 per patient-year). CONCLUSIONS: Changes in HbA1c values were not in favor of insulin monotherapy, compared to regimens including other ADs. It was also associated with higher costs, suggesting that insulin alone is a suboptimal treatment.

Cardiovascular disease prevalence in type 2 diabetes - an analysis of a large German statutory health insurance database.

BACKGROUND: The aim of this study was to determine the prevalence of cardiovascular disease in persons with type 2 diabetes mellitus (T2D) in Germany. METHODS: A claims database with an age- and sex-stratified sample of nearly 4 million individuals insured within the German statutory health system was used. All patients aged ≥18 years with T2D documented between 1 January 2015 and 31 December 2015 and complete retrospective documentation of ≥5 years (continuous enrollment in the German statutory health system) before 2015 were selected based on a validated algorithm. Cardiovascular disease (CVD) events were identified based on ICD-10 and OPS codes according to a previous clinical study (EMPA-REG OUTCOME trial). RESULTS: The prevalence of T2D in Germany in 2015 was 9.9% (n = 324,708). Using a narrow definition of CVD, the 6-year observation period prevalence of CVD was estimated as 46.7% [95% CI: 46.52%;46.86%]. Applying a wider CVD definition, the proportion of T2D patients who showed a history of CVD was 57.1% [95% CI: 56.9%;57.24%]. The prevalence of CVD in patients with T2D ranged from 36.3 to 57.1%, depending on the observation period and definition of CVD. CONCLUSIONS: The results underline the need for a population-based registration of cardiovascular complications in T2D.

The DIVE/DPV registries: evolution of empagliflozin use in clinical practice in Germany.

INTRODUCTION: Empagliflozin reduced morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) in clinical trials. A registry study was undertaken to describe evolution of patient characteristics and assess the real-world effectiveness/safety of empagliflozin. RESEARCH DESIGN AND METHODS: Data from the Diabetes Patienten Verlaufsdokumentation (DPV)/Diabetes Versorgungsevaluation (DIVE) registries on 9571 adults with T2DM (registered in 2014-2019) receiving empagliflozin were used. Patients were grouped according to the following: early users (group 1; n=505) received empagliflozin before the EMPA-REG OUTCOME study publication (mid-September 2015); intermediate users (group 2; n=2961) started empagliflozin after the EMPA-REG OUTCOME publication but before the European Medicines Agency label change (from mid-September 2015 to mid-January 2017); and late users (group 3; n=6105) started empagliflozin after mid-January 2017. Data on clinical and treatment characteristics were collected. RESULTS: Over time, the proportion of recipients aged <65 years decreased (71.1% vs 54.4% among early and late adopters), male patients increased (from 50.9% to 66.5%), body mass index (mean±SD) decreased (from 35.5±6.7 to 32.7±6.6 kg/m2), proportion with cardiovascular morbidities increased (from 20.4% to 26.4%), and mean estimated glomerular filtration rate decreased (from 83.2±19.5 to 78.5±21.1 mL/min/1.73 m2) (all p<0.001). Patients increasingly received empagliflozin in combination with metformin (60.8% vs 68.6% of early and late adopters; p<0.001), glucagon-like peptide-1 (GLP-1) agonists (11.0 vs 14.1%; p<0.001) or insulin (34.3% vs 49.9%; p<0.001). Empagliflozin was generally added to existing antidiabetic regimens. Six months after empagliflozin initiation, the mean glycated hemoglobin (HbA1c) decreased by 0.4%, the proportion of patients with HbA1c <6.5% increased (19.2% vs 12.8%), and the mean fasting plasma glucose decreased (155.8±49.7 vs 168.0±55.1 mg/dL) (all p<0.001). No significant changes in rates of severe hypoglycemia and no cases of diabetic ketoacidosis were seen. CONCLUSIONS: Over time, empagliflozin is being prescribed to a broader patient range in routine practice, is usually added to existing antidiabetic regimens, and is increasingly used in combination with metformin, GLP-1 agonists and/or insulin. Empagliflozin had a beneficial effect on glycemic control, with no increase in hypoglycemia.

Real-world insulin therapy in German type 2 diabetes mellitus patients: patient characteristics, treatment patterns, and insulin dosage.

BACKGROUND: A substantial share of type 2 diabetes mellitus (T2DM) patients receive insulin. However, little is known about the real-world treatment patterns around insulin initiation. METHODS: This was a retrospective claims data analysis. T2DM patients who initiated an insulin therapy between 01/01/2013 and 31/12/2015 were identified in the German AOK PLUS dataset. For validation of results, additional data on a similar T2DM patient population were collected in a Germany-wide medical chart review. RESULTS: A total of 284,878 T2DM patients were identified. Of these, 27,340 (9.6%) initiated an insulin treatment during the inclusion period (mean age: 72.2 years; 51.4% female). Mean/median weight and BMI of patients with available clinical data was 85.8/84.0 kg (SD:18.9) and 30.6/29.8 kg/m2 (SD:6.1), respectively at baseline. Mean/median HbA1c-value at baseline was 8.4/8.0% (SD: 1.8). Most commonly prescribed antidiabetic drugs (AD) within 6 months before insulin initiation were metformin (MET; 54.0%), DPP-4 inhibitors (DPP-4i; 37.6%), and sulfonylureas (SU; 29.5%). As high as 23.2% of the patients did not receive any AD prescription within 6 months before insulin initiation. A total of 10,953 of above 27,340 insulin starters (40.1%) initiated their insulin therapy without concomitant ADs (insulin monotherapy); 43% of these patients did not receive any AD before insulin initiation. Of the remaining 16,387 patients (59.9%), 4070 patients (14.9%) received MET only as concomitant AD, 6385 (23.4%) received MET plus at least one further AD, and 5932 (21.7%) received at least one further AD excluding MET. Throughout the first year of treatment, prescribed insulin dosage increased over time, resulting in approximately 43.3-77.9 IUs per observed patient day after 12 months of insulin treatment. CONCLUSIONS: Characteristics of German T2DM patients initiating insulin deviate substantially from the average German population, especially in terms of weight. We identified an unexpectedly high number of patients without previous AD therapy receiving insulin monotherapy, which is not in line with the clinical guidelines.

Differential effects of C3d on the immunogenicity of gene gun vaccines encoding Plasmodium falciparum and Plasmodium berghei MSP1(42).

The complement fragment C3d mediates B-cell activation via simultaneous engagement of the B-cell receptor and CD21 by antigen/C3d conjugates. Several studies demonstrated the potential of C3d as a molecular adjuvant for vaccination. In this work, C3d exerted differential effects on humoral immune responses after gene gun immunization of mice with plasmids encoding the malaria blood stage antigen MSP1(42) depending on the nature of the protein (Plasmodium falciparum vs. Plasmodium berghei MSP), the localization of the C3d moiety (C-terminal vs. N-terminal), and the presence of putative N-glycosylation sites. No improvement of protective efficacy by C3d attachment or mutation of glycosylation sites could be demonstrated by in vitro parasite growth inhibition assays or in vivo blood stage parasite challenges. Our data underscore the controversial role of C3d as molecular adjuvant.

From sequence to antibody: genetic immunisation is suitable to generate antibodies against a rare plant membrane protein, the KAT 1 channel.

Monoclonal antibodies against the K(+) channel KAT1 of Arabidopsis thaliana, a low abundance, plant plasma membrane protein, were generated by genetic immunisation to avoid the time and labour consuming purification of native or recombinant proteins and peptides usually necessary for conventional immunisation techniques. The resulting polyclonal and monoclonal antibody sera recognised a single protein band in a microsomal fraction of wild-type A. thaliana leaves and in membrane fractions of transgenic yeast cells and tobacco plants expressing the KAT1 protein. Therefore, genetic immunisation is suitable for generating monoclonal antibodies against plant proteins and particularly, against plant membrane proteins of low abundance.

Replicase-based DNA vaccines for allergy treatment.

Replicase-based vaccines were introduced to overcome some of the deficiencies of conventional DNA- and RNA-based vaccines, including poor efficiency and low stability. At ultra-low doses, these alphavirus-derived vectors elicit cellular as well as humoral immune responses. Additionally, replicase-based vectors induce "self-removal" of the vaccine via apoptosis of transfected cells. This chapter describes the construction of a replicon-based DNA vaccine vector from commercially available plasmids. We present protocols for monitoring cellular immune responses following replicase-based immunization including measurement of allergen-specific proliferation of splenocytes, ELISPOT, a FACS-based cytokine secretion assay providing information about T-helper subsets, and a cytokine fluorescent bead immunoassay.

Immunization with a low-dose replicon DNA vaccine encoding Phl p 5 effectively prevents allergic sensitization.

BACKGROUND: Replicase-based DNA vaccines stimulate T(H)1-biased immune responses at ultralow doses and induce self-removal of transfected cells through apoptosis. Both aspects are important requirements for efficient and safe DNA-based immunotherapy of type I allergies. OBJECTIVE: A Sindbis virus replicon-based DNA vaccine encoding the major timothy grass pollen allergen Phl p 5 was evaluated for its antiallergic potential compared with a conventional DNA vaccine in a BALB/c mouse model of allergy. METHODS: Mice were intradermally prevaccinated with plasmid DNA, followed by sensitization and intranasal allergen provocation with recombinant Phl p 5. In vitro proliferation and cytokine secretion was measured in splenocyte cultures. Distribution of IgG1, IgG2a, and IgE antibody subclasses was determined by means of ELISA. IgE-mediated degranulation was measured with the basophil release assay. Bronchoalveolar lavage fluid was analyzed for eosinophils, IL-4, IL-5, IL-13, and IFN-gamma. Mucus production, inflammatory infiltrates, and epithelial damage were determined in lung sections. RESULTS: Both vaccines induced T(H)1-biased immune responses, resulting in suppression of functional IgE, reduction of eosinophilia in bronchoalveolar lavage fluid, and alleviation of lung pathology. However, immunization with the replicon DNA vaccine elicited these effects at a 100-fold lower dose compared with the conventional DNA vaccine. CONCLUSIONS: The increased immunogenicity of replicon-based DNA vaccines allows for application of extremely low doses, thereby eliminating the concerns associated with conventional DNA vaccines, which have to be administered at milligram amounts to induce immune reactions in human subjects. CLINICAL IMPLICATIONS: Their high safety profile makes replicon-based DNA vaccines promising candidates for treatment of type I allergies in the clinic.

Generation of hypoallergenic DNA vaccines by forced ubiquitination: preventive and therapeutic effects in a mouse model of allergy.

BACKGROUND: Hypoallergenic immunotherapy of type I allergies aims at inducing T-cell immunity while avoiding cross-linking of pre-existing IgE. DNA-based immunotherapy depends on the recruitment of antigen-specific T(H)1 cells and therefore has to provide the whole repertoire of T-cell epitopes. Ubiquitination offers a general approach for the production of hypoallergenic DNA vaccines. OBJECTIVE: A DNA-based vaccine encoding the major birch pollen allergen Bet v 1 stably linked to ubiquitin was evaluated for its antiallergic potential in a BALB/c mouse model of allergy. METHODS: Plasmid DNA was applied to mice before (preventive) or after (therapeutic) sensitization with recombinant Bet v 1. In the preventive setting, mice were exposed to aerosolized allergen in addition. Cytokine production was monitored via ELISPOT and Luminex. IgG(1), IgG(2a), and IgE subclass antibody titers were determined by ELISA. In vitro antigen-specific cross-linking of IgE was measured in a degranulation assay. Bronchoalveolar lavages were analyzed for leukocyte subsets as well as for IFN-gamma and IL-5, and paraffin sections of lungs were examined for mucus production and endothelial damage. RESULTS: Prevaccination with ubiquitinated Bet v 1-stimulated T(H)1-biased immune responses with concomitant suppression of functional IgE, reduction of eosinophil counts in bronchoalveolar lavages, and alleviation of lung pathology, and could also suppress an ongoing IgE response in a therapeutic setting. CONCLUSION: The data clearly demonstrate that hypoallergenic DNA vaccines encoding ubiquitin fusion constructs induce effective antiallergic immune responses. CLINICAL IMPLICATIONS: Ubiquitination of allergen gene vaccines eliminates the risk of IgE cross-linking, thereby meeting the safety requirements for clinical applications.

Is genetic vaccination against allergy possible?

Genetic immunization has proven a powerful method to induce antiallergic immune responses. The underlying functional principle has been described to be based on the recruitment of allergen-specific Th1 cells, CD8+ cells and the establishment of a Th1 cytokine milieu, which prevent the development of a Th2-biased response in a protective setup and can balance an ongoing Th2-type response in a therapeutic situation. Genetic immunization with plasmid DNA offers innovative solutions to the major problems associated with protein immunization, such as crosslinking of pre-existing immunoglobulin E on mast cells/basophils or induction of de novo synthesis of immunoglobulin E by the protein immunization itself. It easily enables the routine production of hypoallergenic vaccines, which do not translate native allergens, thus avoiding potential anaphylactic side effects. DNA vaccines can also be applied as mixtures of single vaccines, making them interesting candidates for treatment based on component-resolved diagnosis, followed by an individualized therapy with the relevant allergens. In addition to the description of up-to-date allergen gene vaccine approaches, this review gives an overview of animal studies dealing with the following topics: danger signals as the inherent adjuvant properties, methods to optimize the vaccine immunogenicity, modulation of the immune response, nonparenteral applications and low-dose vaccination strategies.