What to do with diabetes therapies when HbA1c lowering is inadequate:add, switch, or continue? A MASTERMIND study

This is the author accepted manuscript. The final version is available from BioMed Central via the DOI in this record.Background: It is unclear what to do when people with type 2 diabetes have had no or a limited glycemic response to a recently introduced medication. Intra-individual HbA1c variability can obscure true response. Some guidelines suggest stopping apparently ineffective therapy, but no studies have addressed this issue. Methods: In a retrospective cohort analysis using the UK Clinical Practice Research Datalink (CPRD), we assessed the outcome of 55,530 patients with type 2 diabetes starting their second or third non-insulin glucose lowering medication, with a baseline HbA1c >58mmol/mol (7.5%). For those with no HbA1c improvement or a limited response at 6 months (HbA1c fall <5.5mmol/mol [0.5%]) we compared HbA1c 12 months later in those who continued their treatment unchanged, switched to new treatment, or added new treatment. Results: An increase or a limited reduction in HbA1c was common, occurring in 21.9% (12,168/55,230), who had a mean HbA1c increase of 2.5mmol/mol (0.2%). After this limited response, continuing therapy was more frequent (n=9,308; 74%) than switching (n=1,177; 9%) or adding (n=2,163; 17%). Twelve months later, in those who switched medication HbA1c fell (-6.8mmol/mol [-0.6%], 95%CI -7.7, -6.0) only slightly more than those who continued unchanged (-5.1 mmol/mol [-0.5%], 95%CI -5.5, -4.8). Adding another new therapy was associated with a substantially better reduction (-12.4mmol/mol [-1.1%], 95%CI -13.1, -11.7). Propensity score matched subgroups demonstrated similar results. Conclusions: Where glucose lowering therapy does not appear effective on initial HbA1c testing, changing agents does not improve glycemic control. The initial agent should be continued with another therapy added.Medical Research Council (MRC)National Institute for Health Research (NIHR

Physician Associate and General Practitioner Consultations: A Comparative Observational Video Study.

BACKGROUND: Physician associates, known internationally as physician assistants, are a mid-level practitioner, well established in the United States of America but new to the United Kingdom. A small number work in primary care under the supervision of general practitioners, where they most commonly see patients requesting same day appointments for new problems. As an adjunct to larger study, we investigated the quality of the patient consultation of physician associates in comparison to that of general practitioners. METHOD: We conducted a comparative observational study using video recordings of consultations by volunteer physician associates and general practitioners with consenting patients in single surgery sessions. Recordings were assessed by experienced general practitioners, blinded to the type of the consulting practitioner, using the Leicester Assessment Package. Assessors were asked to comment on the safety of the recorded consultations and to attempt to identify the type of practitioner. Ratings were compared across practitioner type, alongside the number of presenting complaints discussed in each consultation and the number of these which were acute, minor, or regarding a chronic condition. RESULTS: We assessed 62 consultations (41 general practitioner and 21 physician associates) from five general practitioners and four physician associates. All consultations were assessed as safe; but general practitioners were rated higher than PAs in all elements of consultation. The general practitioners were more likely than physician associates to see people with multiple presenting complaints (p<0.0001) and with chronic disease related complaints (p = 0.008). Assessors correctly identified general practitioner consultations but not physician associates. The Leicester Assessment Package had limited inter-rater and intra-rater reliability. CONCLUSIONS: The physician associate consultations were with a less complex patient group. They were judged as competent and safe, although general practitioner consultations, unsurprisingly, were rated as more competent. Physician associates offer a complementary addition to the medical workforce in general practice

The disproportionate excess mortality risk of COVID-19 in younger people with diabetes warrants vaccination prioritisation

This is the final version. Available on open access from Springer via the DOI in this recordData availability: CHESS data cannot be shared publicly as it was collected by Public Health England as part of their statutory responsibilities, which allows them to process patient confidential data without explicit patient consent. Data utilised in this study were made available through an agreement between the University of Warwick and Public Health England. Individual requests for access to CHESS data are considered directly by Public Health England (contact via [email protected]).Diabetes U

The impact of population-level HbA1c screening on reducing diabetes diagnostic delay in middle-aged adults: a UK Biobank analysis

This is the final version. Available on open access from Springer via the DOI in this recordData availability: UK Biobank data are available through a procedure described at http://www.ukbiobank.ac.uk/using-the-resource/Aims/hypothesis Screening programmes can detect cases of undiagnosed diabetes earlier than symptomatic or incidental diagnosis. However, the improvement in time to diagnosis achieved by screening programmes compared with routine clinical care is unclear. We aimed to use the UK Biobank population-based study to provide the first population-based estimate of the reduction in time to diabetes diagnosis that could be achieved by HbA1c-based screening in middle-aged adults. Methods We studied UK Biobank participants aged 40–70 years with HbA1c measured at enrolment (but not fed back to participants/clinicians) and linked primary and secondary healthcare data (n=179,923) and identified those with a pre-existing diabetes diagnosis (n=13,077, 7.3%). Among the remaining participants (n=166,846) without a diabetes diagnosis, we used an elevated enrolment HbA1c level (≥48 mmol/mol [≥6.5%]) to identify those with undiagnosed diabetes. For this group, we used Kaplan–Meier analysis to assess the time between enrolment HbA1c measurement and subsequent clinical diabetes diagnosis up to 10 years, and Cox regression to identify clinical factors associated with delayed diabetes diagnosis. Results In total, 1.0% (1703/166,846) of participants without a diabetes diagnosis had undiagnosed diabetes based on calibrated HbA1c levels at UK Biobank enrolment, with a median HbA1c level of 51.3 mmol/mol (IQR 49.1–57.2) (6.8% [6.6–7.4]). These participants represented an additional 13.0% of diabetes cases in the study population relative to the 13,077 participants with a diabetes diagnosis. The median time to clinical diagnosis for those with undiagnosed diabetes was 2.2 years, with a median HbA1c at clinical diagnosis of 58.2 mmol/mol (IQR 51.0–80.0) (7.5% [6.8–9.5]). Female participants with lower HbA1c and BMI measurements at enrolment experienced the longest delay to clinical diagnosis. Conclusions/interpretation Our population-based study shows that HbA1c screening in adults aged 40–70 years can reduce the time to diabetes diagnosis by a median of 2.2 years compared with routine clinical care. The findings support the use of HbA1c screening to reduce the time for which individuals are living with undiagnosed diabetes.Research EnglandNational Institute for Health Research (NIHR)Wellcome Trus

Type 2 Diabetes and COVID-19-Related Mortality in the Critical Care Setting: A National Cohort Study in England, March-July 2020

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this recordOBJECTIVE: To describe the relationship between type 2 diabetes and all-cause mortality among adults with coronavirus disease 2019 (COVID-19) in the critical care setting. RESEARCH DESIGN AND METHODS: This was a nationwide retrospective cohort study in people admitted to hospital in England with COVID-19 requiring admission to a high dependency unit (HDU) or intensive care unit (ICU) between 1 March 2020 and 27 July 2020. Cox proportional hazards models were used to estimate 30-day in-hospital all-cause mortality associated with type 2 diabetes, with adjustment for age, sex, ethnicity, obesity, and other major comorbidities (chronic respiratory disease, asthma, chronic heart disease, hypertension, immunosuppression, chronic neurological disease, chronic renal disease, and chronic liver disease). RESULTS: A total of 19,256 COVID-19-related HDU and ICU admissions were included in the primary analysis, including 13,809 HDU (mean age 70 years) and 5,447 ICU (mean age 58 years) admissions. Of those admitted, 3,524 (18.3%) had type 2 diabetes and 5,077 (26.4%) died during the study period. Patients with type 2 diabetes were at increased risk of death (adjusted hazard ratio [aHR] 1.23 [95% CI 1.14, 1.32]), and this result was consistent in HDU and ICU subsets. The relative mortality risk associated with type 2 diabetes decreased with higher age (age 18-49 years aHR 1.50 [95% CI 1.05, 2.15], age 50-64 years 1.29 [1.10, 1.51], and age ≥65 years 1.18 [1.09, 1.29], P value for age-type 2 diabetes interaction = 0.002). CONCLUSIONS: Type 2 diabetes may be an independent prognostic factor for survival in people with severe COVID-19 requiring critical care treatment, and in this setting the risk increase associated with type 2 diabetes is greatest in younger people.Research EnglandEngineering and Physical Sciences Research Council (EPSRC)University of WarwickNational Institute for Health Research (NIHR)Wellcome Trus

Development of a treatment selection algorithm for SGLT2 and DPP-4 inhibitor therapies in people with type 2 diabetes: a retrospective cohort study

This is the final version. Available from Elsevier via the DOI in this record. Data sharing: CPRD data are available by application to the CPRD Independent Scientific Advisory Committee and clinical trial data are accessible by application to the Yale University Open Data Access Project and Vivli.Background Current treatment guidelines do not provide recommendations to support the selection of treatment for most people with type 2 diabetes. We aimed to develop and validate an algorithm to allow selection of optimal treatment based on glycaemic response, weight change, and tolerability outcomes when choosing between SGLT2 inhibitor or DPP-4 inhibitor therapies. Methods In this retrospective cohort study, we identified patients initiating SGLT2 and DPP-4 inhibitor therapies after Jan 1, 2013, from the UK Clinical Practice Research Datalink (CPRD). We excluded those who received SGLT2 or DPP-4 inhibitors as first-line treatment or insulin at the same time, had estimated glomerular filtration rate (eGFR) of less than 45 mL/min per 1·73 m2, or did not have a valid baseline glycated haemoglobin (HbA1c) measure (<53 or ≥120 mmol/mol). The primary efficacy outcome was the HbA1c value reached 6 months after drug initiation, adjusted for baseline HbA1c. Clinical features associated with differential HbA1c outcome on the two therapies were identified in CPRD (n=26 877), and replicated in reanalysis of 14 clinical trials (n=10 414). An algorithm to predict individual-level differential HbA1c outcome on the two therapies was developed in CPRD (derivation; n=14 069) and validated in head-to-head trials (n=2499) and CPRD (independent validation; n=9376). In CPRD, we further explored heterogeneity in 6-month weight change and treatment discontinuation. Findings Among 10 253 patients initiating SGLT2 inhibitors and 16 624 patients initiating DPP-4 inhibitors in CPRD, baseline HbA1c, age, BMI, eGFR, and alanine aminotransferase were associated with differential HbA1c outcome with SGLT2 inhibitor and DPP-4 inhibitor therapies. The median age of participants was 62·0 years (IQR 55·0–70·0). 10 016 (37·3%) were women and 16 861 (62·7%) were men. An algorithm based on these five features identified a subgroup, representing around four in ten CPRD patients, with a 5 mmol/mol or greater observed benefit with SGLT2 inhibitors in all validation cohorts (CPRD 8·8 mmol/mol [95% CI 7·8–9·8]; CANTATA-D and CANTATA-D2 trials 5·8 mmol/mol [3·9–7·7]; BI1245.20 trial 6·6 mmol/mol [2·2–11·0]). In CPRD, predicted differential HbA1c response with SGLT2 inhibitor and DPP-4 inhibitor therapies was not associated with weight change. Overall treatment discontinuation within 6 months was similar in patients predicted to have an HbA1c benefit with SGLT2 inhibitors over DPP-4 inhibitors (median 15·2% [13·2–20·3] vs 14·4% [12·9–16·7]). A smaller subgroup predicted to have greater HbA1c reduction with DPP-4 inhibitors were twice as likely to discontinue SGLT2 inhibitors than DPP-4 inhibitors (median 26·8% [23·4–31·0] vs 14·8% [12·9–16·8]). Interpretation A validated treatment selection algorithm for SGLT2 inhibitor and DPP-4 inhibitor therapies can support decisions on optimal treatment for people with type 2 diabetes.BHF-Turing Cardiovascular Data Science AwardMedical Research Counci

The hypomethylating agent Decitabine causes a paradoxical increase in 5-hydroxymethylcytosine in human leukemia cells

The USFDA approved "epigenetic drug", Decitabine, exerts its effect by hypomethylating DNA, demonstrating the pivotal role aberrant genome-wide DNA methylation patterns play in cancer ontology. Using sensitive technologies in a cellular model of Acute Myeloid Leukemia, we demonstrate that while Decitabine reduces the global levels of 5-methylcytosine (5mC), it results in paradoxical increase of 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) levels. Hitherto, the only biological mechanism known to generate 5hmC, 5fC and 5caC, involving oxidation of 5mC by members of Ten-Eleven-Translocation (TET) dioxygenase family, was not observed to undergo any alteration during DAC treatment. Using a multi-compartmental model of DNA methylation, we show that partial selectivity of TET enzymes for hemi-methylated CpG dinucleotides could lead to such alterations in 5hmC content. Furthermore, we investigated the binding of TET1-catalytic domain (CD)-GFP to DNA by Fluorescent Correlation Spectroscopy in live cells and detected the gradual increase of the DNA bound fraction of TET1-CD-GFP after treatment with Decitabine. Our study provides novel insights on the therapeutic activity of DAC in the backdrop of the newly discovered derivatives of 5mC and suggests that 5hmC has the potential to serve as a biomarker for monitoring the clinical success of patients receiving DAC

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease

Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10−10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases