Dipeptidyl Peptidase-4 Inhibitor Development and Post-authorisation Programme for Vildagliptin - Clinical Evidence for Optimised Management of Chronic Diseases Beyond Type 2 Diabetes

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.The last decade has witnessed the role of dipeptidyl peptidase-4 (DPP-4) inhibitors in producing a conceptual change in early management of type 2 diabetes (T2DM) by shifting emphasis from a gluco-centric approach to holistically treating underlying pathophysiological processes. DPP-4 inhibitors highlighted the importance of acknowledging hypoglycaemia and weight gain as barriers to optimised care in T2DM. These complications were an integral part of diabetes management before the introduction of DPP-4 inhibitors. During the development of DPP-4 inhibitors, regulatory requirements for introducing new agents underwent substantial changes, with increased emphasis on safety. This led to the systematic collection of adjudicated cardiovascular (CV) safety data, and, where 95% confidence of a lack of harm could not be demonstrated, the standardised CV safety studies. Furthermore, the growing awareness of the worldwide extent of T2DM demanded a more diverse approach to recruitment and participation in clinical trials. Finally, the global financial crisis placed a new awareness on the health economics of diabetes, which rapidly became the most expensive disease in the world. This review encompasses unique developments in the global landscape, and the role DPP-4 inhibitors, specifically vildagliptin, have played in research advancement and optimisation of diabetes care in a diverse population with T2DM worldwide.W David Strain reports grants and personal fees from Novartis, Boehringer Ingelheim, Pfizer and Novo Nordisk during the conducting of the study. Päivi M Paldánius is an employee and shareholder of Novartis. No other potential conflicts of interest relevant to this article were reported. W David Strain acknowledges the support of the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. The views expressed in this publication are those of the authors and not necessarily those of the NIHR Exeter Clinical Research Facility, the National Health Service, the NIHR, or the Department of Health in England. The publication of this article was supported by Novartis Pharma AG

A Review of the Mechanisms, Diagnosis and Preventative Treatment of Osteoporotic Fragility Fractures in Patients With Type 2 Diabetes Mellitus

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The primary association of both type 2 diabetes mellitus (T2DM) and fragility fractures with age has become cause for concern in the developed world, with T2DM now considered an independent risk factor for an increased risk of fragility fracture. The increased susceptibility to fragility fracture associated with T2DM has wide ranging and increasing socioeconomic, morbidity and mortality effects. As the incidence of T2DM increases, understanding the mechanisms behind why T2DM is a causative risk factor to decreased bone health is an important step. These may be split into two broad categories: those that involve an increased risk of falling, and those mechanisms that make fragility fracture after falling more likely due to detrimental changes to bone strength. The latter is not definitively understood making diagnosis in T2DM populations difficult. Current diagnostic methods do not sufficiently account for the unique endocrinological effects of T2DM on bone. New markers for identifying fragility fracture risk in patients with T2DM are required to overcome the paradoxical increase in bone mineral density (BMD) in these populations, and the shortcomings of predictive algorithms and dual energy X-ray absorptiometry (DXA) in identifying fracture risk in T2DM populations. Earlier identification of patients with T2DM who are at risk of fragility fracture is important, as these patients are not as responsive to current preventative medical interventions as those without T2DM, although there are also adoptive lifestyle changes that can help

Individualizing treatment targets for elderly patients with type 2 diabetes: factors influencing clinical decision making in the 24-week, randomized INTERVAL study.

ArticleThis is the final version of the article. Available from Impact Journals via the DOI in this record.We tested the feasibility of setting individualized glycemic goals and factors influencing targets set in a clinical trial in elderly patients with type 2 diabetes. A 24-week, randomized, double-blind, placebo-controlled study was conducted in 45 outpatient centers in seven European countries. 278 drug-naïve or inadequately controlled (mean HbA1c 7.9%) patients with type 2 diabetes aged ≥70 years with HbA1c levels ≥7.0% and ≤10.0% were enrolled. Investigator-defined individualized HbA1c targets and the impact of baseline characteristics on individualized treatment targets was evaluated. The average individualized HbA1c target was set at 7.0%. HbA1c at baseline predicted a target setting such that higher the HbA1c, more aggressive was the target (P<0.001). Men were more likely to be set aggressive targets than women (P=0.026). Frailty status of patients showed a trend towards significance (P=0.068), whereas diabetes duration, age, or polypharmacy did not. There was heterogeneity between countries regarding how baseline factors were viewed. Despite training and guidance to individualize HbA1c goals, targets were still set in line with conventional values. A strong influence of country-specific guidelines on target setting was observed; confirming the importance of further education to implement new international guidelines in older adults.We gratefully acknowledge the INTERVAL study investigators and their staff at 45 participating centers. We also thank Anna Marie Hamann (DATAMAP, GmBH) and Rangan Gupta (Novartis Healthcare Private Limited) for technical and editorial support. WDS would like to acknowledge the support of the National Institute for Health Research (NIHR), Exeter Clinical Research Facility and the NIHR Biomedical Research Centre scheme. WDS is in receipt of a Higher Education Funding Council for the England “New-Blood” Clinical Senior Lectureship award. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. WDS was a member of Peninsula College of Medicine and Dentistry before the demerging of Peninsula into University of Exeter Medical School and Plymouth University Peninsula Schools of Medicine and Dentistry in 2012

Retrospective Database Analysis Evaluating the Clinical Outcomes of Changing Treatment of People with Type 2 Diabetes Mellitus (T2DM) from Other DPP-4 Inhibitor Therapy to Alogliptin in a Primary Care Setting

This is the final version. Available on open access from Springer via the DOI in this recordIntroduction: Although some differences between individual dipeptidyl peptidase-4 (DPP-4) inhibitors may exist, the National Institute for Health and Clinical Excellence (NICE) have recommended that ‘prescribers should be encouraged to select the individual DPP-4 inhibitor with the lowest acquisition cost available to them, where all other factors are equal’. We aimed to determine whether or not ‘within class’ switching to alogliptin, the DPP-4 inhibitor with lowest acquisition cost, is a clinically appropriate strategy. Methods: This study evaluated people with type 2 diabetes taking DPP-4 inhibitor therapy in addition to at least one other diabetes therapy. Primary care records were reviewed from six clinical commissioning groups (CCGs). For people who had been switched from other DPP-4 inhibitors to alogliptin, an assessment of the impact of switch on both absolute haemoglobin A1c (HbA1c) levels and on HbA1c trajectory was undertaken. Persistence on alogliptin and the need for therapy intensification was also assessed. Results: Overall, 865 people with diabetes met the eligibility criteria for the study. There was no significant difference between pre- and post-switch mean HbA1c level [8.44% (SD 1.52%) vs 8.42% (1.62%), p = 0.6]. Similarly, for patients where there was sufficient data to assess the impact of switching on HbA1c trajectory (n = 319) minimal impact was identified (actual HbA1c at 3 months 8.33% vs projected 8.31%). The majority of people with diabetes (80.76%) remained on alogliptin treatment at 6 months and only 4.54% required additional diabetes therapies. Switching to alogliptin resulted in a median saving of £7.24 per patient-month. Conclusion: Switching United Kingdom (UK) primary care patients from other DPP-4 inhibitors to alogliptin did not result in a statistically significant or clinically meaningful change in HbA1c level and few required the addition of further diabetes therapies, suggesting that therapy change or intensification was not considered necessary in most patients who were switched to alogliptin. Trial Registration: ENCePP clinical trial registration number EUPAS29153. Funding: Takeda UK Ltd.National Institute for Health Research (NIHR

A systematic review and meta-analysis of the impact of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiovascular outcomes in biologically healthy older adults

This is the final version. Available on open access from BJDVD Ltd via the DOI in this recordBackground: Unintentional weight loss is a hallmark of frailty and is associated with poor outcomes in older adults with type 2 diabetes. As such, the role of pharmacological therapies that facilitate weight loss – namely, sodiumglucose co-transporter-2 (SGLT-2) inhibitors and glucagonlike peptide-1 (GLP-1) receptor agonists – remains uncertain in fitter older adults. We performed a systematic review and meta-analysis to evaluate these agents on major adverse cardiovascular events (MACE) in older adults eligible for participation in cardiovascular outcome trials. Methods: A literature search was performed in MEDLINE, EMBASE, CINAHL, Cochrane Central Registry of Controlled Trials (CENTRAL) and CNKI from inception to 29 June 2020. A class-specific meta-analysis was conducted in older adults (>65 years at recruitment) and compared with the similar analysis in younger (<65 years) adults. Results: Of 761 unique studies identified, nine met the criteria for inclusion, five using GLP-1 receptor agonists and four with SGLT-2 inhibitors. GLP-1 receptor agonists in older adults were associated with a 15.3% (OR 0.847 (95% CI 0.788 to 0.910)) reduction in MACE events, similar to the 16% benefit seen in younger adults. The use of SGLT-2 inhibitors reduced MACE in older participants by 16.9% (OR 0.831 (95% CI 0.699 to 0.989)), numerically superior to the impact in younger patients (OR 0.936 (95% CI 0.787 to 1.113). Conclusions: GLP-1 receptor agonists and SGLT-2 inhibitors reduced MACE outcomes in older adults who were eligible to participate in clinical trials. Whereas this is reassuring for the biologically robust, it should not be extrapolated to frail older adults without further investigation.National Institute for Health Research (NIHR

Attenuation of microvascular function in those with cardiovascular disease is similar in patients of Indian Asian and European descent

addresses: Institute of Biomedical and Clinical Science, Peninsula Medical School (Exeter), University of Exeter, UK. [email protected]: PMCID: PMC2823616types: Comparative Study; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't© 2010 Strain et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Indian Asians are at increased risk of cardiovascular death which does not appear to be explained by conventional risk factors. As microvascular disease is also more prevalent in Indian Asians, and as it is thought to play a role in the development of macrovascular disease, we decided to determine whether impaired microcirculation could contribute to this increased cardiovascular risk in Indian Asians

Exploring the potential relationships between microvascular haemodynamics and density in bone: a feasibility study utilising near infrared spectroscopy

This is the author accepted manuscript. The final version is available from UKIO2019 via the link in this recordRoyal College of Radiologist

Understanding the barriers and improving care in type 2 diabetes: Brazilian perspective in time to do more in diabetes

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Type 2 diabetes mellitus (T2DM) is a complex disease, particularly in a continental country like Brazil. We attempted to understand and evaluate the perceptions and routines of Brazilians with T2DM and physicians, compared with other countries. METHODS: We compared the results from a 20-min online survey in Brazil with simultaneously collated data from India, Japan, Spain, UK and USA. RESULTS: In total, 652 adults with T2DM and 337 treating physicians were enrolled, of whom 100 patients and 55 physicians were from Brazil. The numbers of primary care physicians from the five countries were 221 versus 43 in Brazil, diabetes specialists were 61 versus 12. There was disconnect between the opinions of physicians and people with diabetes globally. Further, there were differences between clinical practices in Brazil versus the rest of the world, in many areas Brazilians were performing better. CONCLUSIONS: Communication between patients and physicians should be clearer. There is an urgent need to identify the deficits in education, in order to address the clinical inertia within the diabetes management team. There is a necessity to understand the specific requirements of the Brazilian population in order to contextualise international guidelines and implement local changes in practice.The online survey was supported by Novarti

Microalbuminuria could improve risk stratification in patients with TIA and minor stroke.

Published onlineJournal ArticleThis is the final version of the article. Available from Wiley Open Access via the DOI in this record.OBJECTIVE: Transient ischemic attacks (TIA) and minor strokes are important risk factors for recurrent strokes. Current stroke risk prediction scores such as ABCD2, although widely used, lack optimal sensitivity and specificity. Elevated urinary albumin excretion predicts cardiovascular disease, stroke, and mortality. We explored the role of microalbuminuria (using albumin creatinine ratio (ACR)) in predicting recurrence risk in patients with TIA and minor stroke. METHODS: Urinary ACR was measured on a spot sample in 150 patients attending a daily stroke clinic with TIA or minor stroke. Patients were followed up at day 7, 30, and 90 to determine recurrent stroke, cardiovascular events, or death. Eligible patients had a carotid ultrasound Doppler investigation. High-risk patients were defined as those who had an event within 90 days or had >50% internal carotid artery (ICA) stenosis. RESULTS: Fourteen (9.8%) recurrent events were reported by day 90 including two deaths. Fifteen patients had severe ICA stenosis. In total, 26 patients were identified as high risk. These patients had a higher frequency of previous stroke or hypercholesterolemia compared to low-risk patients (P = 0.04). ACR was higher in high-risk patients (3.4 [95% CI 2.2-5.2] vs. 1.7 [1.5-2.1] mg/mmol, P = 0.004), independent of age, sex, blood pressure, diabetes, and previous stroke. An ACR greater than 1.5 mg/mmol predicted high-risk patients (Cox proportional hazard ratio 3.5 (95% CI 1.3-9.5, P = 0.01). INTERPRETATION: After TIA or minor stroke, a higher ACR predicted recurrent events and significant ICA stenosis. Incorporation of urinary ACR from a spot sample in the acute setting could improve risk stratification in patients with TIA and minor stroke.This article presents independent research supported by the NIHR Exeter Clinical Research Facility and the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR Exeter Clinical Research Facility, the NHS, the NIHR or the Department of Health in England. We also acknowledge and thank the South West Stroke Research Network for their help with patient recruitment and follow-up, and Mrs. Audrey Peters and Mr. Frank Summers for performing the carotid Doppler scans

What Next After Metformin in Type 2 Diabetes? Selecting the Right Drug for the Right Patient

This is the final version. Available on open access from Springer via the DOI in this recordIntroduction: Metformin is the recommended initial treatment in type 2 diabetes mellitus (T2DM), but when this does not give adequate glucose control the choice of which second-line drug to use is uncertain as none have been found to have a better overall glycaemic response. In this real-world study dipeptidyl peptidase 4 inhibitors (DPP4i), sulphonylureas (SU), thiazolidinediones (TZD) and sodium glucose co-transporter 2 inhibitors (SGLT2i) were compared for their effectiveness in lowering glycated haemoglobin (HbA1c) levels for a particular individual based on their clinical characteristics. Methods: A retrospective analysis was undertaken of electronic health records of people with T2DM prescribed metformin alongside a DPP4i, SU, TZD or SGLT2i at second-line. Regression modelling was used to model the changes in HbA1c from baseline at month 6 and month 12 for the individual therapies, adjusting for demographic and clinical characteristics. Results: There were 7170 people included in the study. Treatment at second-line with SUs, DPP4i, TZDs and SGLT2i resulted in similar percentages of people achieving the recommended HbA1c target of < 7.5% (58 mmol/mol) at both 6 and 12 months. For those receiving SGLT2i and SUs, the greatest improvement in HbA1c was observed in relatively younger and older people, respectively. Trends were detected between other baseline characteristics and HbA1c improvement by drug class, but they were not statistically significant. Non-adherence rates were low for all drug classes. People with a higher medication possession ratio (≥ 80%) also had greater improvements in HbA1c at 12 months. Conclusion: This study identified patients’ phenotypic characteristics that may have the potential to influence individual treatment response. Accounting for these characteristics in clinical treatment decisions may facilitate individualised prescribing by being able to select the right drug for the right patient.Takeda UK Ltd