Translatability scoring in prospective and retrospective COVID drug development cases.

BACKGROUND: The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 has led to an enormous surge of clinical research. So far, the speed and success rate of related drug development projects, especially of vaccines, is unprecedented. For the first time, this situation allowed for the opportunistic evaluation of a translatability score, originally proposed in 2009, in a prospective manner. METHODS: Several vaccines and treatments under development in clinical phase III trials were selected for translational scoring with the translatability score. Six prospective and six retrospective case studies were performed. The scores had to be determined for a fictive date before any results of the phase III trial were reported in any media. Spearman correlation analysis and a Kruskal Wallis test were performed for statistical evaluation. RESULTS: A significant correlation between the translatability scores and the clinical outcomes in translation was found, as judged on the basis of positive/intermediate/negative endpoint studies or market approval. The Spearman correlation analysis of all cases (r = 0.91, p < 0.001), the prospective cases alone (r = 0.93, p = 0.008), and the retrospective cases alone (r = 0.93, p = 0.008) showed a strong correlation between the score and outcome; R2 demonstrated a score-derived determination of outcomes by 86%. CONCLUSIONS: The score detects strengths and weaknesses of a given project, resulting in the opportunity of selective amelioration of a project, as well as prospective portfolio risk balancing. Its substantial predictive value that has been demonstrated here for the first time could be of particular interest for biomedical industry (pharmaceutical and device manufacturers), funding agencies, venture capitalists, and researchers in the area. Future evaluations will have to address the generalizability of results obtained in an exceptional pandemic situation, and the potential adaptations of weighing factors/items to particular therapeutic areas.

Higher FORTA (Fit fOR The Aged) scores are associated with poor functional outcomes, dementia, and mortality in older people.

PURPOSE: Higher Fit fOR The Aged (FORTA) scores have been shown to be negatively associated with adverse clinical outcomes in older hospitalized patients. This has not been evaluated in other health care settings. The aim of this study was to examine the association of the FORTA score with relevant outcomes in the prospective AgeCoDe-AgeQualiDe cohort of community-dwelling older people. In particular, the longitudinal relation between the FORTA score and mortality and the incidence of dementia was evaluated. METHODS: Univariate and multivariate correlations between the FORTA score and activities of daily living (ADL) or instrumental activities of daily living (IADL) as well as comparisons between high vs. low FORTA scores were conducted. RESULTS: The FORTA score was significantly correlated with ADL/IADL at baseline and at all follow-up visits (p < 0.0001). ADL/IADL results of participants with a low FORTA score were significantly better than in those with high FORTA scores (p < 0.0001). The FORTA score was also significantly (p < 0.0001) correlated with ADL/IADL in the multivariate analysis. Moreover, the mean FORTA scores of participants with dementia were significantly higher (p < 0.0001) than in those without dementia at follow-up visits 6 through 9. The mean FORTA scores of participants who died were significantly higher than those of survivors at follow-up visits 7 (p < 0.05), 8 (p < 0.001), and 9 (p < 0.001). CONCLUSION: In this study, an association between higher FORTA scores and ADL as well as IADL was demonstrated in community-dwelling older adults. Besides, higher FORTA scores appear to be linked to a higher incidence of dementia and even mortality.

Horsefly object-directed polarotaxis is mediated by a stochastically distributed ommatidial subtype in the ventral retina.

The ventral compound eye of many insects contains polarization-sensitive photoreceptors, but little is known about how they are integrated into visual functions. In female horseflies, polarized reflections from animal fur are a key stimulus for host detection. To understand how polarization vision is mediated by the ventral compound eye, we investigated the band-eyed brown horsefly Tabanus bromius using anatomical, physiological, and behavioral approaches. Serial electron microscopic sectioning of the retina and single-cell recordings were used to determine the spectral and polarization sensitivity (PS) of photoreceptors. We found 2 stochastically distributed subtypes of ommatidia, analogous to pale and yellow of other flies. Importantly, the pale analog contains an orthogonal analyzer receptor pair with high PS, formed by an ultraviolet (UV)-sensitive R7 and a UV- and blue-sensitive R8, while the UV-sensitive R7 and green-sensitive R8 in the yellow analog always have low PS. We tested horsefly polarotaxis in the field, using lures with controlled spectral and polarization composition. Polarized reflections without UV and blue components rendered the lures unattractive, while reflections without the green component increased their attractiveness. This is consistent with polarotaxis being guided by a differential signal from polarization analyzers in the pale analogs, and with an inhibitory role of the yellow analogs. Our results reveal how stochastically distributed sensory units with modality-specific division of labor serve as separate and opposing input channels for visual guidance.

Current evidence on the impact of medication optimization or pharmacological interventions on frailty or aspects of frailty: a systematic review of randomized controlled trials.

BACKGROUND: Frailty and adverse drug effects are linked in the fact that polypharmacy is correlated with the severity of frailty; however, a causal relation has not been proven in older people with clinically manifest frailty. METHODS: A literature search was performed in Medline to detect prospective randomized controlled trials (RCTs) testing the effects of pharmacological interventions or medication optimization in older frail adults on comprehensive frailty scores or partial aspects of frailty that were published from January 1998 to October 2019. RESULTS: Twenty-five studies were identified, 4 on comprehensive frailty scores and 21 on aspects of frailty. Two trials on comprehensive frailty scores showed positive results on frailty although the contribution of medication review in a multidimensional approach was unclear. In the studies on aspects related to frailty, ten individual drug interventions showed improvement in physical performance, muscle strength or body composition utilizing alfacalcidol, teriparatide, piroxicam, testosterone, recombinant human chorionic gonadotropin, or capromorelin. There were no studies examining negative effects of drugs on frailty. CONCLUSION: So far, data on a causal relationship between drugs and frailty are inconclusive or related to single-drug interventions on partial aspects of frailty. There is a clear need for RCTs on this topic that should be based on a comprehensive, internationally consistent and thus reproducible concept of frailty assessment.

STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk): a Delphi study by the EuGMS Task and Finish Group on Fall-Risk-Increasing Drugs.

BACKGROUND: Healthcare professionals are often reluctant to deprescribe fall-risk-increasing drugs (FRIDs). Lack of knowledge and skills form a significant barrier and furthermore, there is no consensus on which medications are considered as FRIDs despite several systematic reviews. To support clinicians in the management of FRIDs and to facilitate the deprescribing process, STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk) and a deprescribing tool were developed by a European expert group. METHODS: STOPPFall was created by two facilitators based on evidence from recent meta-analyses and national fall prevention guidelines in Europe. Twenty-four panellists chose their level of agreement on a Likert scale with the items in the STOPPFall in three Delphi panel rounds. A threshold of 70% was selected for consensus a priori. The panellists were asked whether some agents are more fall-risk-increasing than others within the same pharmacological class. In an additional questionnaire, panellists were asked in which cases deprescribing of FRIDs should be considered and how it should be performed. RESULTS: The panellists agreed on 14 medication classes to be included in the STOPPFall. They were mostly psychotropic medications. The panellists indicated 18 differences between pharmacological subclasses with regard to fall-risk-increasing properties. Practical deprescribing guidance was developed for STOPPFall medication classes. CONCLUSION: STOPPFall was created using an expert Delphi consensus process and combined with a practical deprescribing tool designed to optimise medication review. The effectiveness of these tools in falls prevention should be further evaluated in intervention studies.

Calling for an exponential escalation scheme in vaccine development for COVID-19.

PURPOSE: COVID-19 as a pandemic calls for rapid development of vaccines. METHODS: Here a proposal of a seamless, adaptive, phase 1-3 trial for accelerated vaccine development is described. RESULTS: Starting at 10, the number of vaccinated volunteers would exponentially increase by tenfold at an interval of 2 weeks; close surveillance of antibody responses, safety and efficacy is necessary. After only 16 weeks, general vaccination would be feasible if supply meets the demand. CONCLUSION: A COVID-19 vaccine would be rapidly available at a slightly increased risk for undetected late side effects or insufficient efficacy if compared with standard vaccine development schemes.

Mueller matrix characterizations of circularly polarized reflections from golden scarab beetles.

Circularly polarized light (CPL) reflections are rare in nature. Only a few animal groups-most notably certain stomatopod crustaceans and certain beetles in the family Scarabaeidae-are known to reflect CPL from incident unpolarized light. Here, we examine five species of metallic scarabs in the genus Chrysina that, to the naked human eye, look remarkably similar. Using a spectropolarimetric reflectometer to characterize the complete Mueller matrix elements of the beetles' elytral surfaces, we found that four of the five species were strongly left-handed circularly polarized (LHCP), and only one scarab species, Chrysina resplendens, had an overall lower degree of polarization and switched from LHCP to right-handed circularly polarized reflectance depending on wavelength.

A systematic review and novel classification of listing tools to improve medication in older people.

PURPOSE: Suboptimal drugs therapy is a threat to older people, and listing tools providing guidance are developed to address this problem. METHODS: A systematic review was performed to identify and analyze such tools published until February 2018. A novel categorization was developed to separate patient-in-focus listing approaches (PILA) providing disease-related positive and negative guidance from drug-oriented, mostly negative listing approaches (DOLA, DOLA+: with disease specification). RESULTS: In total, 76 tools were identified; only 9 were classified as PILA, 26 as DOLA, and 38 as DOLA+. Three DOLA(+) only address dementia. Most tools were developed in Europe or the USA and address community-dwellers. Thirty-two utilized a Delphi process, and only 10 provide a scoring system. Twenty tools utilize a questionnaire but no structured guidance or answers. Importantly, only 12 interventional clinical trials were identified reporting not only medication quality measures, but also clinical endpoints (e.g. falls, adverse drug reactions, hospitalization). For PILA, 4 trials showed positive, one negative clinical effects of a controlled intervention, for DOLA(+) 1 was positive, 7 negative (Fisher's exact test p < 0.05). DISCUSSION: An abundance of listing tools has been created. DOLAs that may be applied without intricate patient knowledge prevail over PILAs by sevenfold; unfortunately their clinical validation seems to be far less successful than that of patient-initiated approaches. CONCLUSION: Drug therapy in older people has to be tailored to their individual, very divergent needs; tools requiring detailed medical knowledge about the patient as the starting point for medication optimization provide the best support.

Changes in prescription patterns in older hospitalized patients: the impact of FORTA on disease-related over- and under-treatments.

PURPOSE: Physicians often face difficulties in choosing appropriate medications for multimorbid older people. The FORTA (Fit for the Aged) classification (A: absolutely, B: beneficial, C: careful, D: don't) was proposed as a clinical tool for improving the quality of drug treatment in the aged. As an implicit tool, FORTA has been shown to aid medication optimization and improve clinical end points in the VALFORTA trial. In this prospective randomized controlled study, 207 older hospitalized patients received standard geriatric treatment and 202 patients received FORTA-guided treatment. METHODS: Here, changes of drug prescriptions at the anatomical-therapeutic-chemical system (ATC) level were evaluated separately for important diagnoses in descriptive analyses; over- and under-treatment rates were compared between groups. RESULTS: At the individual drug/drug class level related to all important diagnoses, the application of FORTA significantly improved under-treatments for 12 drugs/drug classes (e.g., ACE inhibitors to treat arterial hypertension) and over-treatments for 7 drugs/drug classes (e.g., proton pump inhibitors to treat gastroesophageal reflux disease). CONCLUSIONS: FORTA representing the first combined positive/negative labeling approach at the individual drug level aids the optimization of drug treatment in older people as detected for drugs/drug classes at the ATC level in important indications. FORTA is effective in addressing over- and under-treatments even if analyzed for smaller subgroups of VALFORTA.

Translatability score revisited: differentiation for distinct disease areas.

BACKGROUND: Translational science supports successful transition of early biomedical research into human applications. In 2009 a translatability score to assess risk and identify strengths and weaknesses of a given project has been designed and successfully tested in case studies. The score elements, in particular the contributing weight factors, are heterogeneous for different disease areas; therefore, the score was individualized for six areas (cardiovascular, oncology, psychiatric, anti-viral, anti-bacterial/fungal and monogenetic diseases). RESULTS: FDA reviews and related literature were used for modifications of the score with emphasis on biomarkers, personalized medicine and animal models. 113 new medical entities approved by FDA from 2012 through 2016 were evaluated and metrics obtained for companion diagnostics and animal models as starting points for author-based individualization of the score. Most drugs approved in this period were related to oncology (46%), while the approvals were lowest for psychiatrics (4%). The evaluation of the FDA package inserts revealed that companion diagnostics play an important role in every field except psychiatrics. Further the analysis of the FDA reviews showed the weakness of animal models in psychiatrics and anti-virals, while useful animal models were present for all other fields. Consequently the scoring system was adapted to the different fields, resulting in increased weights for animal models, biomarker and personalized medicine in oncology. For psychiatrics the weights for animal models, biomarker and personalized medicine were decreased, while the weight for model compounds, clinical trials and surrogate or endpoint strategy were increased. For anti-viral drugs weights for in vitro data and personalized medicine were increased, while the weight for animal models was decreased. Further, for anti-bacterial/fungal drugs weights for animal models and personalized medicine were increased. Weights were increased for genetics and personalized medicine and decreased for model compounds for monogenetic orphans. CONCLUSIONS: Adaptation of the score to different disease areas should help to support a structured and diverse approach to translation and encourage researchers in the private or public sectors to further customize the score.

[Drug therapy for older people : Choosing wisely]. / Arzneitherapie des älteren Menschen : "Choosing wisely".

Elderly people are the most rapidly growing sector of our society. Due to their multimorbidity they are exposed to a multitude of medications, which are accompanied by chances and risks. The problem of inappropriate medication in the elderly is exacerbated by the fact that only a holistic view can help these patients and that this is predominantly the responsibility of the general practitioner. The closely measured paid contact time is often insufficient to optimize complex medications. Clinically successfully tested aids in the form of lists give reason for hope: in particular, the positive/negative assessment of limitations of the elderly with respect to drugs by the STOPP/START criteria and the FORTA classification are clinically successful aids. Purely negative lists, such as the Beers or PRISCUS lists, have been disappointing in clinical application because they do not consider the needs, prognostic and particularly symptomatic importance and weighting of the diagnosis of patients. Further implementation of these aids to decision making should help to improve the problem of care of elderly patients in the field of drug treatment, even in IT systems.

Rapid mapping of compound eye visual sampling parameters with FACETS, a highly automated wide-field goniometer.

A highly automated goniometer instrument (called FACETS) has been developed to facilitate rapid mapping of compound eye parameters for investigating regional visual field specializations. The instrument demonstrates the feasibility of analyzing the complete field of view of an insect eye in a fraction of the time required if using non-motorized, non-computerized methods. Faster eye mapping makes it practical for the first time to employ sample sizes appropriate for testing hypotheses about the visual significance of interspecific differences in regional specializations. Example maps of facet sizes are presented from four dipteran insects representing the Asilidae, Calliphoridae, and Stratiomyidae. These maps provide the first quantitative documentation of the frontal enlarged-facet zones (EFZs) that typify asilid eyes, which, together with the EFZs in male Calliphoridae, are likely to be correlated with high-spatial-resolution acute zones. The presence of EFZs contrasts sharply with the almost homogeneous distribution of facet sizes in the stratiomyid. Moreover, the shapes of EFZs differ among species, suggesting functional specializations that may reflect differences in visual ecology. Surveys of this nature can help identify species that should be targeted for additional studies, which will elucidate fundamental principles and constraints that govern visual field specializations and their evolution.

Measurement of dabigatran, rivaroxaban and apixaban in samples of plasma, serum and urine, under real life conditions. An international study.

BACKGROUND: The utility of measuring non-vitamin K antagonist oral anticoagulants (NOACs) in plasma, serum and urine samples and with the point-of-care test (POCT) on urine samples should be analysed in an international laboratory study. METHODS: The study was performed to determine the inter-laboratory variance of data from two chromogenic assays each for the NOACs rivaroxaban, apixaban and dabigatran, and to analyse the sensitivity and specificity of the POCT assays for factor Xa- and thrombin inhibitors. Plasma, serum and urine samples were taken from six patients in each group on treatment with a NOAC. RESULTS: The inter-laboratory variances, which can be identified best by the coefficient of variation, ranged from 46% to 59% for apixaban, 63% to 73% for rivaroxaban and 39% to 104% for dabigatran using plasma, serum or urine samples and two chromogenic assays for each NOAC. The concentrations were about 20% higher in serum compared to plasma samples for apixaban and rivaroxaban, and 60% lower for dabigatran. The concentration in urine samples was five-fold (apixaban), 15-fold (rivaroxaban) and 50-fold (dabigatran) higher. Sensitivity and specificity of POCT for apixaban, rivaroxaban, and dabigatran were all >94%. CONCLUSIONS: The inter-laboratory study showed the feasibility of measurement of apixaban, rivaroxaban, and dabigatran in plasma, serum and urine samples of patients on treatment. Dabigatran was determined at far lower levels in serum compared to plasma samples. Concentrations of NOACs in urine were much higher compared to plasma. The POCT was highly sensitive and specific for all three NOACs.

VALFORTA: a randomised trial to validate the FORTA (Fit fOR The Aged) classification.

TRIAL DESIGN: to further validate the FORTA (Fit fOR The Aged) concept, a bicentric randomised, controlled trial was run in two geriatric clinics. METHODS: patients (≥65 years, ≥3 drugs or ≥60 years, ≥6 drugs) with three relevant diseases and hospitalisation for ≥5 days were randomised. In the intervention, but not the control group, a FORTA team instructed ward physicians on FORTA. FORTA is the first positive/negative listing approach labelling medications used to treat chronic illnesses in older patients from A (indispensable), B (beneficial), C (questionable) to D (avoid). The primary end point was the FORTA score: sum of medication errors classified as over-, under- and mistreatment. Consecutive patients were randomised to the intervention and control ward; outcome assessment was blinded. RESULTS: four hundred and nine patients (age 81.5 years, 64% female, hospitalisation 17.4 days) were included. The primary end point was significantly (P < 0.0001) more reduced in the intervention versus control groups (2.7 ± 2.25 versus 1 ± 1.8, mean ± SD, intergroup comparison of admission/discharge differences). Over- and under-treatment scores and use of A (increase) and D (decrease) drugs were significantly improved (P < 0.01). The total number of adverse drug reactions (ADRs) was significantly reduced by FORTA (P < 0.05, number needed to treat is 5). Activities of daily living and renal failure improved significantly (P < 0.05). Blood pressure remained constant in the intervention, but decreased significantly in the control group. CONCLUSION: applying FORTA to hospitalised geriatric patients leads to improvement of medication quality and may improve secondary clinical end points (e.g. ADRs). The concept is amenable to successful communication and implementation. Registration (DRKS-ID): DRKS00000531. FUNDING: DFG-German Research Foundation (WE 1184/15-1).

[New oral anticoagulants for prophylaxis of stroke. Results of an expert conference on practical use in geriatric patients]. / Neue orale Antikoagulanzien zur Prophylaxe von Schlaganfällen. Ergebnis einer Expertenkonferenz zum praktischen Einsatz bei geriatrischen Patienten.

Geriatric patients with non-valvular atrial fibrillation (AF) are increasingly being treated with novel oral anticoagulants (NOAC) to prevent ischemic stroke. This article highlights the outcome of an expert meeting on the practical use of NOAC in elderly patients. An interdisciplinary group of experts discussed the current situation of stroke prevention in geriatric patients and its practical management in daily clinical practice. The topic was examined through focused impulse presentations and critical analyses as the basis for the expert consensus. The key issues are summarized in this paper. The European Society of Cardiology (ESC) guidelines from 2012 for the management of patients with non-valvular AF recommend NOAC as the preferred treatment and vitamin K antagonists (VKA) only as an alternative option. Currently, the NOAC factor Xa inhibitors apixaban and rivaroxaban and the thrombin inhibitor dabigatran are more commonly used in clinical practice for patients with AF. Although these drugs have many similarities and are often grouped together it is important to recognize that the pharmacology and dose regimes differ between compounds. Especially n elderly patients NOAC drugs have some advantages compared to VKA, e.g. less drug-drug interactions with concomitant medication and a more favorable risk-benefit ratio mostly driven by the reduction of bleeding. Treatment of anticoagulation in geriatric patients requires weighing the serious risk of stroke against an equally high risk of major bleeding and pharmacoeconomic considerations. Geriatric patients in particular have the greatest benefit from NOAC, which can also be administered in cases of reduced renal function. Regular control of the indications is indispensable, as also for all other medications of the patient. The use of NOAC should certainly not be withheld from geriatric patients who have a clear need for oral anticoagulation.

Patients' serum and urine as easily accessible samples for the measurement of non-vitamin K antagonist oral anticoagulants.

Measurement of the anticoagulant effect of non-vitamin K antagonist oral anticoagulants (NOAC) may be desirable, in particular in patients with acute medical conditions. Useful methods should give results rapidly within minutes, should be easy to perform, specific, and sensitive. Using plasma samples, chromogenic assays can be made to be specific for the two types of NOAC (factor Xa and thrombin inhibitors), and also hemoclot and ecarin clotting time specific for dabigatran. If plasma samples anticoagulated with sodium citrate are not available, blood samples anticoagulated with ethylene diamine tetraacetic acid or serum samples may be regarded as alternatives for the determination of NOAC. At present, dabigatran cannot be determined from serum samples because it may be consumed during the clotting process to obtain serum. NOAC can be determined in urine samples due to their renal elimination. Quantitative methods are preferable to qualitative methods, although the latter may be advantageous in some situations, being developed as point-of-care tests for oral factor Xa and thrombin inhibitors. In these tests, the presence and absence of NOAC in urine can be identified with the naked eye after a few minutes and these tests are highly specific and sensitive. New assays such as a semiquantitative determination in urine samples and measurement using other sample matrices are currently under development.

Development of recommendations to continue anticoagulation with one of the two types of oral anticoagulants based on the identification of patients' preference.

Patients with indication for anticoagulation may prefer treatment with a vitamin K antagonist (VKA) or non-vitamin K antagonist oral anticoagulant (NOAC). A questionnaire may help to identify the preference of patients for one of the two types of oral anticoagulants and to develop a score for the recommendation to continue or to change the anticoagulant. A score was developed using a questionnaire containing biographic data and eight statements on attitudes on anticoagulation and was derived to trigger continuation or change the type of anticoagulant by defining ranges of terms and weighting of the significant statements identified by logistic regression analysis. Participating patients received either anticoagulation with VKA (group 1, n = 690), were transferred from VKA to NOAC (group 2, n = 158), received NOAC de novo (group 3, n = 137) or were transferred from NOAC to VKA (group 4, n = 19). Four statements were significantly (p values between 0.0347 and < 0.0001) associated with recommendations to maintain or to change the type of anticoagulant for patients in groups 1, 2, or 3 with predictive values of c = 0.83 between groups 1 and 2 and c = 0.71 between groups 1 and 3. From the total number of replies to the statements a score of three grades and two strengths (A = strong, B = moderate) was derived for the recommendations. This tool supports recommendations as to continue or to change the presently used type of oral anticoagulant based on the identification of patients' preferences.

Treatment-dependent and treatment-independent risk factors associated with the risk of diabetes-related events: a retrospective analysis based on 229,042 patients with type 2 diabetes mellitus.

BACKGROUND: The aim of this study was to analyse which factors predict the real-world macro-/microvascular event, hospitalisation and death risk in patients with type 2 diabetes mellitus. Furthermore, we aimed to investigate whether there exists both an under- and over-treatment risk of these patients. METHODS: We used a German claims/clinical data set covering the years 2010-12. Diabetes-related events were defined as (1) macro-, (2) microvascular events leading to inpatient hospitalisation, (3) other hospitalisations with type 2 diabetes mellitus as main diagnosis, (4) all-cause death and (5) a composite outcome including all event categories 1-4. Factors associated with event risk were analysed by a Kaplan-Meier curve analysis and by multivariable Cox regression models. RESULTS: 229,042 patients with type 2 diabetes mellitus (mean age 70.2 years; mean CCI 6.03) were included. Among factors that increased the event risk were patients' age, male gender, the adapted Charlson Comorbidity Index, the adapted Diabetes Complication Severity Index, previous events, and number of prescribed chronic medications. For systolic blood pressure/HbA1C, a double-J/U-curve pattern was detected: HbA1C of 6-6.5% (42-48 mmol/mol) and systolic blood pressure of 130-140 mmHg (17.3-18.7kPa) were associated with the lowest event risk, values below/above that range were associated with higher risk. However, this pattern was mainly driven by the death risk and was much less clearly observed for the macrovascular/microvascular/hospitalization risk and for young/less comorbid patients. CONCLUSIONS: Both blood pressure and HbA1C seem to be very important treatment targets, especially in comorbid old patients. It is of particular clinical importance that both over- and under-treatment pose a threat to patients with type 2 diabetes mellitus.