Dr Martin Whyte

Associate Professor of Metabolic Medicine
+44 (0)1483 688669
21 PG 00
Mon to Wed

Academic and research departments

School of Biosciences.


Areas of specialism

Type 2 diabetes mellitus; Insulin resistance; Cardiovascular disease

University roles and responsibilities

  • Faculty MD co-ordinator
  • Department PGR co-ordinator

    My qualifications

    BSc Physiology with Basic Medical Sciences
    King's College London
    King's College Hospital School of Medicine & Dentistry
    Royal College of Physicians
    King's College London
    Higher Education Academy
    Royal College of Physicians
    'The Metabolic Effects of Intensive Insulin Therapy in Critically Ill Patients'



    Research interests


    Postgraduate research supervision




    Disparities in glycaemic control, monitoring and treatment in type 2 diabetes: a retrospective cohort analysis

    Martin Whyte, William Hinton, Andrew McGovern, Jeremy van Vlymen, Filipa Ferreira, Silvio Calderara, Julie Mount, Neil Munro, Simon de Lusignan

    PLoS Medicine Oct 2019; 16 (10), e1002942


    R.Mahmud, A.Gray, A.Nabeebaccus, M.B.Whyte (2018) Incidence and outcomes of long QTc in acute medical admissions.
    Int J Clinical Practice 2018 Nov;72(11):e13250. doi: 10.1111/ijcp.13250.


    Prolonged QT interval on electrocardiogram (ECG) increases the risk of ventricular arrhythmia. Patients admitted to acute medical units (AMU) may be at risk of QT prolongation from multiple, recognised risk factors. Few data exist regarding incidence or outcomes of QT prolongation in acute general medical admissions. The aims were to determine the incidence of Bazett's-corrected QT (QTc) prolongation upon admission to AMU; the relationship between QTc and inpatient mortality, length of stay and readmission; proportion with prolonged QTc subsequently administered QT interval-prolonging drugs.


    Retrospective, observational study of 1000 consecutive patients admitted to an AMU in a large urban hospital.


    age <18 years, ventricular pacing, poor quality/absent ECG. QTc determined manually from ECG obtained within 4-hours of admission. QTc prolongation considered ≥470 milliseconds (males) and ≥480 milliseconds (females). In both genders, >500 milliseconds was considered severe. Study end-points, (a) incidence of QTc prolongation at admission; (b) inpatient mortality, length of stay and readmission rates; (c) proportion with QTc prolongation subsequently administered QT interval-prolonging drugs.


    Of 1000 patients, 288 patients were excluded, therefore final sample was n = 712. Patient age (mean ± SD) was 63.1 ± 19.4 years; females 49%. QTc prolongation was present in n = 50 (7%) at admission; 1.7% had QTc interval >500 ms. Of the 50 patients admitted with prolonged QTc, 6 (12%) were subsequently administered QT interval-prolonging drugs. QTc prolongation was not associated with worse inpatient mortality or readmission rate. Length of stay was greater in those with prolonged QTc, 7.2 (IQR 2.4-13.2) days vs 3.3 (IQR 1.3-10.0; P = 0.004), however, in a regression model, presence of QTc did not independently affect length of stay.


    QTc interval prolongation is frequent among patients admitted to AMU. QT interval-prolonging drugs are commonly prescribed to patients presenting with prolonged QTc but whether this affects clinical outcomes is uncertain

    McGovern A, Tippu Z, Hinton W, Munro N, Whyte M, de Lusignan S (2017) Comparison of medication adherence and persistence in type 2 diabetes: A systematic review and meta-analysis
    Diabetes Obes Metab. 2018 Apr;20(4):1040-1043. doi: 10.1111/dom.13160. Epub 2017 Dec 12.

    Limited medication adherence and persistence with treatment are barriers to successful management of type 2 diabetes (T2D). We searched MEDLINE, EMBASE, the Cochrane Library, the Register of Controlled Trials, PsychINFO and CINAHL for observational and interventional studies that compared the adherence or persistence associated with 2 or more glucose‐lowering medications in people with T2D. Where 5 or more studies provided the same comparison, a random‐effects meta‐analysis was performed, reporting mean difference (MD) or odds ratio (OR) for adherence or persistence, depending on the pooled study outcomes. We included a total of 48 studies. Compared with metformin, adherence (%) was better for sulphonylureas (5 studies; MD 10.6%, 95% confidence interval [CI] 6.5‐14.7) and thiazolidinediones (TZDs; 6 studies; MD 11.3%, 95% CI 2.7%‐20.0%). Adherence to TZDs was marginally better than adherence to sulphonylureas (5 studies; MD 1.5%, 95% CI 0.1‐2.9). Dipeptidyl peptidase‐4 inhibitors had better adherence than sulphonylureas and TZDs. Glucagon‐like peptide‐1 receptor agonists had higher rates of discontinuation than long‐acting analogue insulins (6 studies; OR 1.95; 95% CI 1.17‐3.27). Long‐acting insulin analogues had better persistence than human insulins (5 studies; MD 43.1 days; 95% CI 22.0‐64.2). The methods used to define adherence and persistence were highly variable.

    Chris Woodmansey, Andrew McGovern, Katherine McCullough, Martin Whyte, Neil Munro, Ana Correa, Piers Gatenby, Simon Jones, Simon de Lusignan (2017) Incidence, demographics and clinical characteristics of diabetes following pancreatic disease: a retrospective cohort study. Diabetes Care 2017;40(11):1486-1493. doi: 10.2337/dc17-0542


    This study was conducted to describe the incidence of diabetes following pancreatic disease, assess how these patients are classified by clinicians, and compare clinical characteristics with type 1 and type 2 diabetes.


    Primary care records in England (n = 2,360,631) were searched for incident cases of adult-onset diabetes between 1 January 2005 and 31 March 2016. We examined demographics, diabetes classification, glycemic control, and insulin use in those with and without pancreatic disease (subcategorized into acute pancreatitis or chronic pancreatic disease) before diabetes diagnosis. Regression analysis was used to control for baseline potential risk factors for poor glycemic control (HbA1c ≥7% [53 mmol/mol]) and insulin requirement.


    We identified 31,789 new diagnoses of adult-onset diabetes. Diabetes following pancreatic disease (2.59 [95% CI 2.38-2.81] per 100,000 person-years) was more common than type 1 diabetes (1.64 [1.47-1.82]; P < 0.001). The 559 cases of diabetes following pancreatic disease were mostly classified by clinicians as type 2 diabetes (87.8%) and uncommonly as diabetes of the exocrine pancreas (2.7%). Diabetes following pancreatic disease was diagnosed at a median age of 59 years and BMI of 29.2 kg/m2. Diabetes following pancreatic disease was associated with poor glycemic control (adjusted odds ratio, 1.7 [1.3-2.2]; P < 0.001) compared with type 2 diabetes. Insulin use within 5 years was 4.1% (3.8-4.4) with type 2 diabetes, 20.9% (14.6-28.9) with diabetes following acute pancreatitis, and 45.8% (34.2-57.9) with diabetes following chronic pancreatic disease.


    Diabetes of the exocrine pancreas is frequently labeled type 2 diabetes but has worse glycemic control and a markedly greater requirement for insulin.

    Boughton CK, Munro N, Whyte M (2017) Targeting beta-cell preservation in the management of type 2 diabetes. British Journal of Diabetes Dec 2017; 17: 134-144

    Type 2 diabetes (T2D) is widely considered a chronic and progressive disease without cure. As beta-cell function progressively declines over time, blood glucose rises. Current management of T2D involves incremental introduction of dietary and drug therapies to achieve normoglycaemia. However, recent studies have demonstrated remission of T2D following bariatric surgery, very low calorie diet or intensive insulin therapy, raising the possibility that the declining beta-cell function in T2D may be arrested or even reversed. The point at which such interventions are introduced in the course of T2D is key for clinical benefit. Future treatment strategies should be revised to target early beta-cell preservation and thus disease remission. This article reviews the pathogenesis of beta-cell dysfunction and evidence for the clinical benefit of preserving beta-cell function in T2D, and discusses the evidence for beta-cell preservation of current glucose-lowering therapies with particular reference to their effect when initiated at the time of diagnosis of T2D.

    Olubukola Ajala; Freda Mold; Charlotte Boughton; Debbie Cooke; Martin Whyte (2017) Childhood predictors of cardiovascular disease in adulthood. A systematic review and meta-analysis. Obesity Reviews 2017 May 25th. doi: 10.1111/obr.12561

    Childhood obesity predicts the risk of adult adiposity, which is associated with the earlier onset of cardiovascular disease [adult atherosclerotic cardiovascular disease, ACVD: hypertension, increased carotid intima media thickness (CIMT) stroke, ischemic heart disease (IHD)] and dysglycaemia. Because it is not known whether childhood obesity contributes to these diseases, we conducted a systematic review of studies that examine the ability of measures of obesity in childhood to predict dysglycaemia and ACVD. Data sources were Web of Science, MEDLINE, PubMed, CINAHL, Cochrane, SCOPUS, ProQuest and reference lists. Studies measuring body mass index (BMI), skin fold thickness and waist circumference were selected; of 1,954 studies, 18 met study criteria. Childhood BMI predicted CIMT: odds ratio (OR), 3.39 (95% confidence interval (CI), 2.02 to 5.67, P < 0.001) and risk of impaired glucose tolerance in adulthood, but its ability to predict ACVD events (stroke, IHD; OR, 1.04; 95% CI, 1.02 to 1.07; P < 0.001) and hypertension (OR, 1.17, 95% CI 1.06 to 1.27, P = 0.003) was weak-moderate. Body mass index was not predictive of systolic BP (r -0.57, P = 0.08) and weakly predicted diastolic BP (r 0.21, P = 0.002). Skin fold thickness in childhood weakly predicted CIMT in female adults only (rs 0.09, P < 0.05). Childhood BMI predicts the risk of dysglycaemia and abnormal CIMT in adulthood, but its ability to predict hypertension and ACVD events was weak and moderate, respectively. Skin fold thickness was a weak predictor of CIMT in female adults.

    E. Lioudaki, E. Androulakis, M. Whyte, K. Stylianou, E. Daphnis, E. Ganotakis (2017) Renal effects of SGLT-2 inhibitors and other anti-diabetic drugs: Clinical relevance and potential risks. Clinical Pharmacology & Therapeutics 2017 May 8. doi: 10.1002/cpt.731

    Type 2 diabetes mellitus (T2DM) is a metabolic disease affecting an increasing percentage of general population worldwide. Patients with T2DM are frequently characterized by impaired renal function, primarily as a result of diabetic kidney injury, but also by other contributing factors, such as hypertension, atherosclerosis, and medications. Sodium-glucose cotransporter (SGLT)-2 inhibitors have emerged as a new, promising class of antidiabetic agents with actions that seem to extend beyond their hypoglycemic effect.

    E. Lioudaki, E. Androulakis, M. Whyte, K. Stylianou, E. Daphnis, E. Ganotakis (2017) The effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on cardiometabolic profile; beyond the hypoglycaemic action. Cardiovascular Drugs and Therapy 2017 April 25th. doi: 10.1007/s10557-017-6724-3.

    Type 2 diabetes mellitus (T2DM) has growing prevalence worldwide and major clinical implications, chiefly cardiovascular (CV) and renal disease burden. Sodium-glucose co-transporter (SGLT)-2 inhibitors are a new drug class in the management of T2DM with a mechanism of action independent of insulin. In addition to their hypoglycaemic effect, SGLT-2 inhibitors appear to have haemodynamic and nephroprotective effects. Studies have consistently showed a modest but significant blood pressure (BP) reduction. Metabolic benefits are also attributed to SGLT-2 inhibitors with a modest but consistent body weight decrease recorded along with improvements in lipid profile and uric acid levels. Remarkable findings of significant cardioprotective effects came from the recent EMPA-REG study with a particular focus on heart failure. In the kidney, SGLT-2 inhibitors reduce hyperfiltration, a precipitant of diabetic nephropathy.

    Katie Schwab, Ralph Smith, Vanessa Brown, Martin Whyte, Iain Jourdan (2017) Evolution of stereoscopic imaging in surgery and recent advances
    World J of Gastrointestinal Endoscopy 2017; 9(8): 368-377

    In the late 1980s the first laparoscopic cholecystectomies were performed prompting a sudden rise in technological innovations as the benefits and feasibility of minimal access surgery became recognised. Monocular laparoscopes provided only two-dimensional (2D) viewing with reduced depth perception and contributed to an extended learning curve. Attention turned to producing a usable three-dimensional (3D) endoscopic view for surgeons; utilising different technologies for image capture and image projection. These evolving visual systems have been assessed in various research environments with conflicting outcomes of success and usability, and no overall consensus to their benefit. This review article aims to provide an explanation of the different types of technologies, summarise the published literature evaluating 3D vs 2D laparoscopy, to explain the conflicting outcomes, and discuss the current consensus view.

    Mae Johnson, Martin Whyte, Robert Loveridge, Richard Yorke, Shairana Naleem (2017) A unified form for CPR and Treatment Escalation Plan improves communication and early collaborative decision making for acute hospital admissions. BMJ Quality Improvement Reports 2017;6:u213254.w6626. doi:10.1136/bmjquality. u213254.w6626

    The National Confidential Enquiry into Patient Outcomes and Death (NCEPOD) report ‘Time to Intervene’ (2012) stated that in a substantial number of cases, resuscitation is attempted when it was thought a ‘do not attempt cardiopulmonary resuscitation’ (DNACPR) decision should have been in place. Early decisions about CPR status and advance planning about limits of care now form part of national recommendations by the UK Resuscitation Council (2016).

    Treatment escalation plans (TEP) document what level of treatment intervention would be appropriate if a patient were to become acutely unwell and were not previously formally in place at King's College Hospital. A unifying paper based form was successfully piloted in the Acute Medical Unit, introducing the TEP and bringing together decision making around both treatment escalation and CPR status. Subsequently an electronic order-set for CPR status and treatment escalation was launched in April 2015 which led to a highly visible CPR and escalation status banner on the main screen at the top of the patient's electronic record.

    Ultimately due to further iterations in the electronic process by December 2016, all escalation decisions for acutely admitted patients now have high quality supporting, explanatory documentation with 100% having TEPs in place.

    There is now widespread multidisciplinary engagement in the process of defining limits of care for acutely admitted medical patients within the first 14 hours of admission and a strategy for rolling this process out across all the divisions of the hospital through our Deteriorating Patient Group (DPG).

    The collaborative design with acute medical, palliative and intensive care teams and the high visibility provided by the electronic process in the Electronic Patient Record (EPR) has enhanced communication with these teams, patients, nursing staff and the multidisciplinary team by ensuring clarity through a universally understood process about escalation and CPR.

    Clarity and openness about these discussions have been welcomed by patient focus groups facilitated via our acute medicine patient experience committee. There has been a shift in medical culture where transparency about limits of care has contributed to improving patient safety and quality of care through reducing unnecessary CPR supported by focus groups of staff.

    McGovern A, Hinton W, Correa A, Munro N, Whyte M, de Lusignan S (2016) Real world evidence studies into treatment adherence, thresholds for intervention, and disparities in treatment, in people with Type 2 Diabetes in the UK. BMJ Open 2016; 6:e012801 doi:10.1136/bmjopen-2016-012801

    Purpose The University of Surrey-Lilly Real World Evidence (RWE) diabetes cohort has been established to provide insights into the management of type 2 diabetes mellitus (T2DM). There are 3 areas of study due to be conducted to provide insights into T2DM management: exploration of medication adherence, thresholds for changing diabetes therapies, and ethnicity-related or socioeconomic-related disparities in management. This paper describes the identification of a cohort of people with T2DM which will be used for these analyses, through a case finding algorithm, and describes the characteristics of the identified cohort.

    Participants A cohort of people with T2DM was identified from the Royal College of General Practitioners Research and Surveillance Centre (RCGP RSC) data set. This data set comprises electronic patient records collected from a nationally distributed sample of 130 primary care practices across England with scope to increase the number of practices to 200.

    Findings to date A cohort (N=58 717) of adults with T2DM was identified from the RCGP RSC population (N=1 260 761), a crude prevalence of diabetes of 5.8% in the adult population. High data quality within the practice network and an ontological approach to classification resulted in a high level of data completeness in the T2DM cohort; ethnicity identification (82.1%), smoking status (99.3%), alcohol use (93.3%), glycated haemoglobin (HbA1c; 97.9%), body mass index (98.0%), blood pressure (99.4%), cholesterol (87.4%) and renal function (97.8%). Data completeness compares favourably to other, similarly large, observational cohorts. The cohort comprises a distribution of ages, socioeconomic and ethnic backgrounds, diabetes complications, and comorbidities, enabling the planned analyses.

    Future plans Regular data uploads from the RCGP RSC practice network will enable this cohort to be followed prospectively. We will investigate medication adherence, explore thresholds and triggers for changing diabetes therapies, and investigate any ethnicity-related or socioeconomic-related disparities in diabetes management

    Louise M Goff, Martin B Whyte, Miriam Samuel, Scott Harding (2016) Significantly greater triglyceridemia in Blacks compared to Whites following high fructose and glucose feeding: a randomized crossover trial. Lipids in Health & Disease 2016; 15(1): 145


    Black African (BA) populations are losing the cardio-protective lipid profile they historically exhibited, which may be linked with increasing fructose intakes. The metabolic effects of high fructose diets and how they relate to blood lipids are documented for Caucasians, but have not been described in BA individuals.


    The principle objective of this pilot study was to assess the independent impacts of high glucose and fructose feeding in men of BA ancestry compared to men of White European (WE) ancestry on circulating triglyceride (TG) concentrations.


    Healthy males, aged 25–60 years, of BA (n = 9) and WE (n = 11) ethnicity were randomly assigned to 2 feeding days in a crossover design, providing mixed nutrient meals with 20 % total daily caloric requirements from either added glucose or fructose. Circulating TG, non-esterified fatty acids (NEFA), glucose, insulin and C-peptide were measured over two 24-h periods.


    Fasting TGs were lower in BAs than WEs on the fructose feeding day (p < 0.05). There was a trend for fasting TG concentrations 24 h following fructose feeding to increase in both BA (baseline median fasting: 0.80, IQR 0.6–1.1 vs 24-h median post-fructose: 1.09, 0.8–1.4 mmol/L; p = 0.06) and WE (baseline median fasting 1.10, IQR 0.9–1.5 vs 24-h median post-fructose: 1.16, IQR 0.96–1.73 mmol/L; p = 0.06). Analysis within ethnic group demonstrated that in TG iAUC was significantly higher in BA compared to WE on both glucose (35, IQR 11–56 vs −4, IQR −10–1 mmol/L/min; p = 0.004) and fructose (48, IQR 15–68 vs 13, IQR −7–38 mmol/L/min; p = 0.04). Greater suppression of postprandial NEFA was evident in WE than BA after glucose feeding (−73, IQR −81– −52 vs −26, IQR −48– −3 nmol/L/min; p = 0.001) but there was no ethnic difference following fructose feeding.


    Understanding the metabolic effects of dietary acculturation and Westernisation that occurs in Black communities is important for developing prevention strategies for chronic disease development. These data show postprandial hypertriglyceridemia following acute feeding of high added fructose and glucose in BA men, compared to WE men, may contribute to metabolic changes observed during dietary acculturation and Westernisation

    Martin Whyte, Roisin Johnson, Deborah Cooke, Kathryn Hart, Marie McCormack, Jill Shawe (2016) Diagnosing gestational diabetes mellitus in women following bariatric surgery: A national survey of lead diabetes midwives
    Br J Midwifery


    Bariatric surgery is becoming more common among women of fertile age to manage obesity. The number of pregnancies following bariatric surgery is, therefore, likely to rise. The standard oral glucose tolerance test (OGTT) may lead to dizziness, sweating and collapse in people after some types of bariatric surgery.



    In view of this potential pitfall in the diagnosis of gestational diabetes mellitus (GDM) after bariatric surgery, the authors surveyed midwifery units to establish current practice for the screening and diagnosis of GDM in women who have had bariatric surgery.



    Out of 164 English obstetric units, 120 email surveys were sent to a network of lead diabetes midwives in units across England.

    A reminder email was sent 4 weeks later.



    Twenty-seven (22.5%) responses were received. Five respondents (26%) had specific policies in place to manage pregnancies after bariatric surgery. A wide variety of approaches to GDM screening and diagnosis were used in women with a history of bariatric surgery. The OGTT was the most widely used test after bariatric surgery.



    There is a need for national clinical guidelines to be developed for the diagnosis of GDM after bariatric surgery.

    Edison E, Whyte M, van Vlymen J, Jones S, Gatenby P, de Lusignan S, Shawe J (2016) Bariatric surgery in obese women of reproductive age improves conditions that underlie fertility and pregnancy outcomes: retrospective cohort study of UK National Bariatric Surgery Registry (NBSR). Obesity Surgery 2016 Dec;26(12):2837-2842


    The aims of this study are the following: to describe the female population of reproductive age having bariatric surgery in the UK, to assess the age and ethnicity of women accessing surgery, and to assess the effect of bariatric surgery on factors that underlie fertility and pregnancy outcomes.


    Demographic details, comorbidities, and operative type of women aged 18–45 years were extracted from the National Bariatric Surgery Registry (NBSR). A comparison was made with non-operative cases (aged 18–45 and BMI ≥40 kg/m2) from the Health Survey for England (HSE, 2007–2013). Analyses were performed using “R” software.


    Data were extracted on 15,222 women from NBSR and 1073 from HSE. Women aged 18–45 comprised 53 % of operations. Non-Caucasians were under-represented in NBSR compared to HSE (10 vs 16 % respectively, p < 0.0001). The NBSR group was older than the HSE group—median 38 (IQR 32–42) vs 36 (IQR 30–41) years (Wilcoxon test p < 0.0001). Almost one third of women in NBSR had menstrual dysfunction at baseline (33.0 %). BMI fell in the first year postoperatively from 48.2 ± 8.3 to 37.4 ± 7.5 kg/m2 (t test, p < 0.001). From NBSR, in the postoperative period, the prevalence of type 2 diabetes fell by 54 %, polycystic ovarian syndrome by 15 %, and any menstrual dysfunction by 12 %.


    Over half of all bariatric procedures are carried out on women of reproductive age. More work is required to provide prompt and equal access across ethnic groups. At least one in three women suffers from menstrual dysfunction at baseline. Bariatric surgery improves factors that underlie fertility and pregnancy outcomes. A prospective study is required to verify these effects

    E. Lioudaki, M.B.Whyte (2016) Acute cardiac decompensation in a patient with beta-thalassemia and diabetes mellitus following cessation of chelation therapy. Clinical Case Reports 2016; 4(10): 992-996

    Patients with higher liver iron stores are likely to have a worse cardiac outcome following noncompliance with chelation. Cardiovascular magnetic resonance identifies myocardial siderosis allowing optimization of iron chelation regimes. Diabetes puts thalassemic patients at increased risk of myocardial fibrosis. Dual chelation therapy with deferoxamine and deferiprone offers improved cardiac outcomes.

    McGovern A, Tippu Z, Hinton W, Munro N, Whyte M, de Lusignan S (2016) A systematic review of adherence rates by medication class in type 2 diabetes: Study protocol. BMJ Open 2016; 6:e010469 doi:10.1136/bmjopen-2015-010469

    Introduction Treatment options for type 2 diabetes are becoming increasingly complex with people often prescribed multiple medications, and may include both oral and injectable therapies. There is ongoing debate about which drug classes provide the optimum second-line and third-line treatment options. In the real world, patient adherence and persistence determines medication effectiveness. A better understanding of adherence may help inform the choice of second-line and third-line drug classes.

    Methods and analysis This systematic review will compare adherence and persistence rates across the different classes of medication available to people with type 2 diabetes. It will include all identified studies comparing medication adherence or persistence between two or more glucose-lowering medications in people with type 2 diabetes. Research databases (MEDLINE, EMBASE, The Cochrane Library, The Register of Controlled Trials, PsychINFO and CINAHL) will be searched for relevant articles, using a comprehensive search strategy. All identified medication trials and observational studies will be included which compare adherence or persistence across classes of diabetes medication. The characteristics and outcomes of all the included studies will be reported along with a study quality grade, assessed using the Cochrane Risk Assessment Tool. The quality of adjustment for confounders of adherence or persistence will be reported for each study. Where multiple (n ≥3) studies provide compare adherence or persistence across the same 2 medication classes, a meta-analysis will be performed.

    Ethics and dissemination No ethics approval is required. This review and meta-analysis (where possible) will provide important information on the relative patient adherence and persistence, with the different classes of diabetes therapies. Once complete, the results will be made available by peer-reviewed publication.

    MB Whyte, CA Manu, D Hopkins, S Thomas (2015) Evidence of patient self-testing at clinic review: association with glycaemic control. Br J Diab Vasc Dis 2015;15(2):75-77.
    M.B.Whyte, A.Quaglia, D.Hopkins (2015) Insulin detemir may be less efficacious in patients with non-alcoholic fatty liver disease and hypertriglyceridaemia. Clinical Case Reports Dec 2015

    Insulin detemir is commonly used in obese patients with diabetes mellitus as it is considered hepatoselective and causes less weight gain. We describe a relative lack of effectiveness of detemir in patients with significant NAFLD and hypertriglyceridemia, compared to isophane insulin. This may affect how such patients are managed with insulin.

    MB Whyte, S Pramodh, L Srikugan, JA Gilbert, JP Miell, RA Sherwood, AM McGregor, SJB Aylwin (2015) Importance of cannulated prolactin test in the definition of hyperprolactinaemia. Pituitary 2015;18(3): 319-25

    Purpose: Recent guidelines suggest that a single prolactin measurement is adequate to confirm hyperprolactinaemia. This may lead to unnecessary investigation of artefactual hyperprolactinaemia. Prolactin measurement drawn from an indwelling cannula after rest removes stress as a confounding variable. The objective was to determine the frequency of true hyperprolactinaemia amongst patients referred following a single prolactin measurement.

    Methods: A cannulated study was considered if prolactin on referral ('Referral Prolactin') was <5,500 mU/L (260 ng/mL) but >410 mU/L (19 ng/mL) in males or >510 mU/L (24 ng/mL) in females, irrespective of clinical context. Case-notes of 267 patients undergoing cannulated prolactin measurement over a 10-year period (2000-2010) were reviewed. Pre-existing pituitary disease, dopamine antagonist use, and macroprolactinaemia were excluded. Morning ante-cubital vein cannulation was followed immediately by withdrawal of 'Repeat Prolactin' sample. After 120-min bed-rest, 'Resting Prolactin' was withdrawn through the cannula.

    Results: 235 patients were included for analysis. 64 (27%) were within normal range; following Repeat Prolactin in 41 (17%) and Resting Prolactin in 23 (9%) cases. Referral Prolactin was higher in patients with true hyperprolactinaemia, 1,637 ± 100 mU/L (77.2 ± 4.7 ng/mL) than with artefactual hyperprolactinaemia, 1,122 ± 68 mU/L (52.9 ± 3.2 ng/mL; P < 0.001) but there was substantial overlap. 21 out of 171 cases (12%) with true hyperprolactinaemia had a macroadenoma. Presenting symptoms did not predict true hyperprolactinaemia. Referral Prolactin of 2,000 mU/L (94 ng/mL) had 97% specificity to identify true hyperprolactinaemia.

    Conclusions: Reliance on a single, non-rested prolactin value may lead to over-diagnosis of hyperprolactinaemia. A resting sample should be considered with random values <2,000 mU/L (94 ng/mL).

    M.B.Whyte, S Velusamy, SJB Aylwin (2014) Disease severity and staging of obesity: A rational approach to patient selection. Current Atherosclerosis Reports 2014 Nov;16(11):456. doi: 10.1007/s11883-014-0456-7.

    The increasing prevalence of obesity places ever-increasing cost demands on healthcare systems. One million individuals are eligible for bariatric surgery in the UK, and yet less than 6000 bariatric procedures are performed annually. Bariatric surgery reverses or improves almost all the medical and psychosocial co-morbidities associated with obesity. Although the BMI is a simple method to estimate adiposity at a population level, it is relatively inaccurate within an individual and provides little-to-no indication of overall health status or disease severity. Staging systems overcome the inherent limitations of BMI and allow highly informed decision-making for an individual. At a societal level, this helps to identify those most likely to gain and maximise economic benefit. This review summarises the co-morbidities associated with obesity and the evidence for their improvement following surgery. The rationale for new staging criteria and appropriate patient selection are discussed.

    I.Karageorgiou, C Chandler, MB Whyte (2014) Silent diabetes mellitus, periodontitis, and a new case of thalamic abscess. BMJ Case Reports 2014 Jul 21;2014:bcr2014204654. doi: 10.1136/bcr-2014-204654.

    Brain abscess is an unusual complication of uncontrolled diabetes. A solitary thalamic abscess is an uncommon type of brain abscess. We report a case of thalamic abscess, whereupon diabetes mellitus and periodontitis were diagnosed. The diagnosis and management of thalamic abscess, and the interplay of type 2 diabetes and periodontitis are discussed. A 56-year-old, Caucasian, man with no medical or travel history, presented with 5-day symptoms of meningeal irritation. Body mass index 30.6 kg/m(2). CT demonstrated a solitary midline lesion with neoplasia as a differential diagnosis. It was biopsied and cultures grew Streptococcus milleri. He was treated by stereotactic puncture, external drainage and targeted intrathecal and systemic antibiotic therapy. HIV negative but glycated haemoglobin (HbA1c) 10.7% (93 mmol/mol). Dental examination revealed a small molar abscess. Radiological resolution of the thalamic abscess occurred within 2 months. Diabetes improved with 7 weeks of insulin, and maintained on metformin, HbA1c 6.9% (51 mmol/mol). There was no residual neurological disability

    L.Lee, W.I. Sung, M.M. Akhtar, M. Whyte (2012) Diaphoresis and abdominal pain caused by extra-adrenal paraganglionomas. BMJ Case Reports. 2012 Jul 3;2012:bcr0120125649. doi: 10.1136/bcr.01.2012.5649

    A 63-year-old lady presented with suprapelvic pain, weight loss and night sweats. On examination, she was noted to be hypertensive with a distended abdomen. Imaging (CT) revealed a 9.5 cm retroperitoneal mass with a high degree of vascularity and necrotic centre. The patient's urinary and plasma catecholamines were significantly raised and subsequent radio-isotope scan suggested the tumour was likely to be of a neuroendocrine nature. A diagnosis of a malignant paraganglioma was made. Malignant paragangliomas derive from sympathetic tissue and secrete catecholamines. Diagnostic uncertainty might lead to biopsy of tumour but this carries a high-risk of catecholamine-induced complications such as hypertensive crisis, cardiac arrhythmias and cardiac ischaemia and must be avoided.

    M. Whyte, N. Jackson, F. Shojaee-Moradie, R. Beale, D. Treacher, R.H.Jones, A.M. Umpleby (2010) The Metabolic Effects of Intensive Insulin Therapy in Critically Ill Patients. Am J Physiol 2010; 298(3): E697 - E705.

    Our aim was to investigate the effects of glycemic control and insulin concentration on lipolysis, glucose, and protein metabolism in critically ill medical patients. For our methods, the patients were studied twice. In study 1, blood glucose (BG) concentrations were maintained between 7 and 9 mmol/l with intravenous insulin. After study 1, patients entered one of four protocols for 48 h until study 2: low-insulin high-glucose (LIHG; variable insulin, BG of 7-9 mmol/l), low-insulin low-glucose (LILG; variable insulin of BG 4-6 mmol/l), high-insulin high-glucose [HIHG; insulin (2.0 mU . kg(-1).min(-1) plus insulin requirement from study 1), BG of 7-9 mmol/l], or high-insulin low-glucose [HILG; insulin (2.0 mU.kg(-1).min(-1) plus insulin requirement from study 1), BG of 4-6 mmol/l]. Age-matched healthy control subjects received two-step euglycemic hyperinsulinemic clamps achieving insulin levels similar to the LI and HI groups. In our results, whole body proteolysis was higher in patients in study 1 (P < 0.006) compared with control subjects at comparable insulin concentrations and was reduced with LI (P < 0.01) and HI (P = 0.001) in control subjects but not in patients. Endogenous glucose production rate (R(a)), glucose disposal, and lipolysis were not different in all patients in study 1 compared with control subjects at comparable insulin concentrations. Glucose R(a) and lipolysis did not change in any of the study 2 patient groups. HI increased glucose disposal in the patients (HIHG, P = 0.001; HILG, P = 0.07 vs. study 1), but this was less than in controls receiving HI (P < 0.03). In conclusion, low-dose intravenous insulin administered to maintain BG between 7-9 mmol/l is sufficient to limit lipolysis and endogenous glucose R(a) and increase glucose R(d). Neither hyperinsulinemia nor normoglycemia had any protein-sparing effect.

    Marwood S, Constantin-Teodosiou D, Casey E, Whyte M, Boobis L, Bowtell J (2010) No Acetyl Group deficit is evident at the onset of exercise at 90% of maximal oxygen uptake in humans. J Sports Sci 2010;28(3):267-79. doi: 10.1080/02640410903440884

    The existence of an acetyl group deficit at or above 90% of maximal oxygen uptake (VO(2max)) has proved controversial, with contradictory results likely relating to limitations in previous research. The purpose of the present study was to determine whether the "acetyl group deficit" occurs at the start of exercise at 90%VO(2max) in a well-controlled study. Eight male participants (age: 33.6 +/- 2.0 years; VO(2max): 3.60 +/- 0.21 litres . min(-1)) completed two exercise bouts at 90%VO(2max) for 3 min following either 30 min of saline (control) or dichloroacetate (50 mg . kg(-1) body mass) infusion, ending 15 min before exercise. Muscle biopsies were obtained immediately before and after exercise while continuous non-invasive measures of pulmonary oxygen uptake and muscle deoxygenation were made. Muscle pyruvate dehydrogenase activity was significantly higher before exercise following dichloroacetate infusion (control: 2.67 +/- 0.98 vs. dichloroacetate: 17.9 +/- 1.1 mmol acetyl-CoA . min(-1) . mg(-1) protein, P = 0.01) and resulted in higher pre- and post-exercise muscle acetylcarnitine (pre-exercise control: 3.3 +/- 0.95 vs. pre-exercise dichloroacetate: 8.0 +/- 0.88 vs. post-exercise control: 11.9 +/- 1.1 vs. post-exercise dichloroacetate: 17.2 +/- 1.1 mmol . kg(-1) dry muscle, P < 0.05). However, substrate-level phosphorylation (control: 125 +/- 20 vs. dichloroacetate: 113 +/- 13 mmol adenosine triphosphate . kg(-1) dry muscle) and VO(2) kinetics (control: 19.2 +/- 2.2 vs. dichloroacetate: 22.8 +/- 2.5 s), were unaltered. Furthermore, dichloroacetate infusion blunted the slow component of VO(2) and muscle deoxygenation and slowed muscle deoxygenation kinetics, possibly by enhancing oxygen delivery during exercise. These data support the hypothesis that the "acetyl group deficit" does not occur at or above 90%VO(2max).

    M.Whyte, C.Down, J.Miell, M.Crook. (2009) Lack of laboratory assessment of severe hyponatraemia is associated with detrimental clinical outcomes in hospitalised patients. Int J Clin Practice 2009; 63(10): 1451 - 1455 doi: 10.1111/j.1742-1241.2009.02037.x.

    Objective: Increased mortality with severe hyponatraemia is well known. What is less clear is the mortality risk according to the pattern of the developing hyponatraemia and whether this may be affected by the intervention of the clinician.

    Methods: From our laboratory database, we retrospectively collected data of a 12-month period of adult patients with severe hyponatraemia (< or = 120 mmol/l). One hundred and thirteen patients were identified. Normonatraemic controls (n = 113) were identified by plasma sodium of 135 mmol/l over the same period, and whose nadir during hospitalisation was > or = 130 mmol/l. Results are mean +/- SD unless stated otherwise. Duration of hospitalisation and clinical outcomes was confirmed from hospital records.

    Results: The mean nadir plasma sodium of the hyponatraemic group was 116.0 +/- 4.4 mmol/l and 134.0 +/- 2.8 mmol/l in controls. Although the hyponatraemic patients were younger than controls (65.8 +/- 18.4 vs. 72.3 +/- 14.9 years; p = 0.004), they had higher mortality (24 vs. 7, p = 0.002) and longer hospitalisation than controls: median (IQR), 12 (7-22) vs. 7 (3-16.5) days (p < 0.001). A total of 55 patients developed severe hyponatraemia following admission. This subgroup comprised a higher proportion of surgical patients (23.6% vs. 1.7%, p < 0.001) than those with severe hyponatraemia on admission. Furthermore, both mortality (n = 17 vs. n = 7; p = 0.02) and duration of hospitalisation, median 19 days (IQR 10-35) vs. 9.5 (5-15) days (p < 0.001), were greater. Failure to measure plasma and urinary osmolalities was associated with increased mortality.

    Conclusions: Severe hyponatraemia is associated with prolonged admission and increased mortality compared with normonatraemic patients. Progressive hyponatraemia following admission incurs a higher risk of death. This may represent illness-severity, inappropriate management or inadequate investigation.

    Shojaee-Moradie F, Baynes KCR, Pentecost C, Bell JD, Thomas EL, Jackson NC, Stolinski M, Whyte M, Lovell D, Bowes SB, Gibney J, Jones RH, Umpleby AM. (2007) Exercise training reduces fatty acid availability and improves insulin sensitivity of glucose metabolism. Diabetologia 2007; 50(2): 404 - 413.


    It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables.


    We randomised 17 sedentary overweight male subjects (age 50 +/- 2.6 years, BMI 27.6 +/- 0.5 kg/m(2)) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic-euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg(-1) min(-1)]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning.


    After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group.


    Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise

    Giannoulis MG, Sonksen PH, Umpleby M, Breen L, Pentecost C, Whyte M, McMillan CV, Bradley C, Martin FC. (2006) The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab 2006; 91(2): 477 - 484


    Declines in GH and testosterone (Te) secretion may contribute to the detrimental aging changes of elderly men.


    To assess the effects of near-physiological GH with/without Te administration on lean body mass, total body fat, midthigh muscle cross-section area, muscle strength, aerobic capacity, condition-specific quality of life (Age-Related Hormone Deficiency-Dependent Quality of Life questionnaire), and generic health status (36-Item Short-Form Health Survey) of older men.


    A 6-month, randomized, double-blind, placebo-controlled trial was performed on 80 healthy, community-dwelling, older men (age, 65-80 yr).


    Participants were randomized to receive 1) placebo GH or placebo Te, 2) recombinant human GH (rhGH) and placebo Te (GH), 3) Te and placebo rhGH (Te), or 4) rhGH and Te (GHTe). GH doses were titrated over 8 wk to produce IGF-I levels in the upper half of the age-specific reference range. A fixed dose of Te (5 mg) was given by transdermal patches.


    Lean body mass increased with GHTe (P = 0.008) and GH (P = 0.004), compared with placebo. Total body fat decreased with GHTe only (P = 0.02). Midthigh muscle (P = 0.006) and aerobic capacity (P < 0.001) increased only after GHTe. Muscle strength changes were variable; one of six measures significantly increased with GHTe. Significant treatment group by time interactions indicated an improved Age-Related Hormone Deficiency-Dependent Quality of Life questionnaire score (P = 0.007) in the GH and GHTe groups. Bodily pain increased with GH alone, as determined by the Short-Form Health Survey (P = 0.003). There were no major adverse effects.


    Coadministration of low dose GH with Te resulted in beneficial changes being observed more often than with either GH or Te alone.

    Martin B Whyte, Fariba Shojaee-Moradie, Sharaf E Sharaf, Nicola C Jackson, Barbara Fielding, Roman Hovorka, Jeewaka Mendis, David Russell-Jones, Margot Umpleby (2018) Lixisenatide reduces chylomicron triacylglycerol due to increased clearance. Journal of Clinical Endocrinology & Metabolism. 11 September 2018


    GLP-1 agonists control postprandial glucose and lipid excursion in type 2 diabetes; however the mechanism(s) are unclear.


    To determine the mechanism(s) of postprandial lipid and glucose control with lixisenatide (GLP-1 analogue) in type 2 diabetes.


    Randomised, double-blind, cross-over study.


    Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, UK


    Eight obese men with type 2 diabetes (57.3±1.9yrs; BMI 30.3±1.0kg/m2, HbA1C 66.5±2.6mmol/mol, [8.2±0.3%]).


    Two metabolic studies, four-weeks after lixisenatide or placebo; with cross-over and repetition of studies.

    Main outcome measures

    Study one: very-low density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with iv bolus of [2H5]glycerol in a 12h study, with hourly feeding. Oral [13C]triolein, in a single meal, labelled enterally-derived TAG.

    Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable iv [6,6-2H2]glucose infusion.


    Study one: CM-TAG (but not VLDL-TAG) pool-size, was lower with lixisenatide (P=0.046). Lixisenatide reduced CM [13C]oleate AUC60-480min concentration (P=0.048) and increased CM-TAG clearance; with no effect on CM-TAG production rate.

    Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P=0.0051, P<0.05). Total glucose production rate (Ra) (P=0.015), Rameal (P=0.0098) and acetaminophen AUC0-360min (P=0.006) were lower with lixisenatide than placebo.


    Lixisenatide reduced [13C]oleate concentration, derived from a single meal in CM-TAG, as well as glucose Rameal, through delayed gastric emptying. However day-long CM production, measured with repeated meal-feeding, was not reduced by lixisenatide and decreased CM-TAG concentration was due to increased CM-TAG clearance.

    Philip Kelly, Martin Whyte (2018) The normal range: it’s not normal and it’s not a range.
    Postgraduate Medical Journal Nov 2018 November 2018. doi: 10.1136/postgradmedj-2018-135983

    The NHS ‘Choose Wisely’ campaign places greater emphasis on the clinician-patient dialogue. Patients are often in receipt of their laboratory data and want to know whether they are normal. But what is meant by normal? Comparator data, to a measured value, are colloquially known as the ‘normal range’. It is often assumed that a result outside this limit signals disease and a result within health. However, this range is correctly termed the ‘reference interval’. The clinical risk from a measured value is continuous, not binary. The reference interval provides a point of reference against which to interpret an individual’s results—rather than defining normality itself. This article discusses the theory of normality—and describes that it is relative and situational. The concept of normality being not an absolute state influenced the development of the reference interval. We conclude with suggestions to optimise the use and interpretation of the reference interval, thereby facilitating greater patient understanding

    Martin B Whyte, Neil Munro (2019) Changing the care pathway for Type 2 diabetes at the time of diagnosis: the role of the multidisciplinary team.
    Diabetic Medicine 2019 May;36(5):653-654

    Conventionally, specialists become involved in the later stages of Type 2 diabetes mellitus, whereas evidence supports the role of time‐limited specialist input at the start of treatment journey. The diagnosis of Type 2 diabetes should be seen as a key opportunity for multidisciplinary teams to intensify therapy aimed at quickly correcting underlying metabolic dysfunction.

    Mustafa OG, Whyte MB (2019) The use of GLP-1 receptor agonists in hospitalised patients: an untapped potential
    Diabetes/Metabolism Research & Reviews. 2019 May 29:e3191. doi: 10.1002/dmrr.3191. [Epub ahead of print]

    In the outpatient setting, Glucagon‐like peptide‐1 (GLP‐1) receptor agonists have proved to be highly efficacious drugs that provide glycaemic control with a low risk of hypoglycaemia. These characteristics make GLP‐1 receptor agonists attractive agents to treat dysglycaemia in perioperative or high‐dependency hospital settings; where glycaemic variability and hyperglycaemia are associated with poor prognosis. GLP‐1 also has a direct action on the myocardium and vasculature ‐ which may be advantageous in the immediate aftermath of a vascular insult. This is a narrative review of the work in this area.


    The aim was to determine the populations of hospitalised patients being evaluated and the clinical and mechanistic end‐points tested, with the institution of GLP‐1 therapy in hospital. We searched the PubMed, Embase, and Google scholar databases, combining the term ‘glucagon‐like peptide 1’ OR ‘GLP‐1’ OR ‘incretin’ OR ‘liraglutide’ OR ‘exenatide’ OR ‘lixisenatide’ OR ‘dulaglutide’ OR ‘albiglutide’ AND ‘inpatient’ OR ‘hospital’ OR ‘perioperative’ OR ‘postoperative’ OR ‘surgery’ OR ‘myocardial infarction’ OR ‘stroke’ OR ‘cerebrovascular disease’ OR ‘transient ischaemic attack’ OR ‘ICU’ OR ‘critical care’ OR ‘critical illness’ OR ‘CCU’ OR ‘coronary care unit’.


    Pilot studies were reported in the fields of acute stroke, cardiac resuscitation, coronary care and perioperative care that showed advantages for GLP‐1 therapy; with normalisation of glucose, lower glucose variability and lower risk of hypoglycaemia. Animal and human studies have reported improvements in myocardial performance when given acutely after vascular insult or surgery, but these have yet to be translated into randomised clinical trials.

    Simon de Lusignan, William Hinton, Emmanouela Konstantara, Neil Munro, Martin Whyte, Julie Mount, Michael Feher (2019) Intensification to injectable therapy in type 2 diabetes: mixed methods study (protocol).
    BMC Health Services Research 2019; 19:284
    M Dunstan, R Smith, KE Schwab, A Scala, P Gatenby, MB Whyte, TA Rockall, IC Jourdan (2019) Is 3D faster and safer than 4K laparoscopic cholecystectomy? A randomised-controlled trial
    Surgical Endoscopy 2019; Apr;34(4):1729-1735 doi: 10.1007/s00464-019-06958-w.

    Background: Laparoscopic surgery has well-established benefits for patients; however, laparoscopic procedures have a long and difficult learning curve, in large part due to the lack of stereoscopic depth perception. Developments in high-definition and stereoscopic imaging have attempted to overcome this. Three-dimensional high-definition (3D HD) systems are thought to improve operating times compared to two-dimensional high-definition systems. However their performance against new, ultra-high-definition ('4K') systems is not known.

    Methods: Patients undergoing laparoscopic cholecystectomy were randomised to 3D HD or 4K laparoscopy. Operative videos were recorded, and the time from gallbladder exposure to separation from the liver (minus on table cholangiogram) was calculated. Blinded video assessment was performed to calculate intraoperative error scores.

    Results: One hundred and twenty patients were randomised, of which 109 were analysed (3D HD n = 54; 4K n = 55). No reduction in operative time was detected with 3D HD compared to 4K laparoscopy (median [IQR]; 23.41 min [17.00-37.98] vs 20.90 min [17.67-33.03]; p = 0.91); nor was there any decrease observed in error scores (60 [56-62] vs 58 [56-60]; p = 0.27), complications or reattendance. Stone spillage occurred more frequently with 3D HD, but there were no other differences in individual error rates. Gallbladder grade and operating surgeon had significant effects on time to complete the operation. Gallbladder grade also had a significant effect on the error score.

    Conclusions: A 3D HD laparoscopic system did not reduce operative time or error scores during laparoscopic cholecystectomy compared with a new 4K imaging system.

    Schwab KE, Curtis NJ, Whyte MB, Smith R, Rockall TA, Ballard K, Jourdan IC (2019) 3D laparoscopy does not reduce operative duration or errors in day case laparoscopic cholecystectomy: A randomised controlled trial.
    Surgical Endoscopy 2019 Jul 16. doi: 10.1007/s00464-019-06961-1.


    Contemporary 3D platforms have overcome past deficiencies. Available trainee and laboratory studies suggest stereoscopic imaging improves performance but there is little clinical data or studies assessing specialists. We aimed to determine whether stereoscopic (3D) laparoscopic systems reduce operative time and number of intraoperative errors during specialist-performed laparoscopic cholecystectomy (LC).


    A parallel arm (1:1) randomised controlled trial comparing 2D and 3D passive-polarised laparoscopic systems in day-case LC using was performed. Eleven consultant surgeons that had each performed > 200 LC (including > 10 3D LC) participated. Cases were video recorded and a four-point difficulty grade applied. The primary outcome was overall operative time. Subtask time and the number of intraoperative consequential errors as identified by two blinded assessors using a hierarchical task analysis and the observational clinical human reliability analysis technique formed secondary endpoints.


    112 patients were randomised. There was no difference in operative time between 2D and 3D LC (23:14 min (± 10:52) vs. 20:17 (± 9:10), absolute difference − 14.6%, p = 0.148) although 3D surgery was significantly quicker in difficulty grade 3 and 4 cases (30:23 min (± 9:24), vs. 18:02 (± 7:56), p < 0.001). No differences in overall error count was seen (total 47, median 1, range 0–4 vs. 45, 1, 0–3, p = 0.62) although there were significantly fewer 3D gallbladder perforations (15 vs. 6, p = 0.034).


    3D laparoscopy did not reduce overall operative time or error frequency in laparoscopic cholecystectomies performed by specialist surgeons. 3D reduced Calot’s dissection time and operative time in complex cases as well as the incidence of iatrogenic gallbladder perforation (NCT01930344).

    Shawe J, Ceulemans D, Akhter Z, Neff K, Hart K, Heslehurst N, Stotl I, Agrawal S, Steegers R, Taheri S, Greenslade B, Rankin J , Huda B, Douek I, Ogden J, Galjaard S, Blumenfeld O, Robinson A, Whyte M, Murphy E, Wood C, Devlieger R. (2019) Pregnancy after bariatric surgery: consensus recommendations for periconception, antenatal and postnatal care.
    Obesity Reviews 2019 Nov; 20(11): 1507-1522

    The objective of the study is to provide evidence‐based guidance on nutritional management and optimal care for pregnancy after bariatric surgery. A consensus meeting of international and multidisciplinary experts was held to identify relevant research questions in relation to pregnancy after bariatric surgery. A systematic search of available literature was performed, and the ADAPTE protocol for guideline development followed. All available evidence was graded and further discussed during group meetings to formulate recommendations. Where evidence of sufficient quality was lacking, the group made consensus recommendations based on expert clinical experience. The main outcome measures are timing of pregnancy, contraceptive choice, nutritional advice and supplementation, clinical follow‐up of pregnancy, and breastfeeding. We provide recommendations for periconception, antenatal, and postnatal care for women following surgery. These recommendations are summarized in a table and print‐friendly format. Women of reproductive age with a history of bariatric surgery should receive specialized care regarding their reproductive health. Many recommendations are not supported by high‐quality evidence and warrant further research. These areas are highlighted in the paper.

    Martin B Whyte (2019) Is high-density lipoprotein a modifiable treatment target or just a biomarker for cardiovascular disease?
    JRSM Cardiovascular Disease 2019 Aug 12. doi: 10.1177/2048004019869736

    Epidemiological data strongly support the inverse association between high-density lipoprotein cholesterol concentration and cardiovascular risk. Over the last three decades, pharmaceutical strategies have been partially successful in raising high-density lipoprotein cholesterol concentration, but clinical outcomes have been disappointing. A recent therapeutic class is the cholesteryl ester transfer protein inhibitor. These drugs can increase circulating high-density lipoprotein cholesterol levels by inhibiting the exchange of cholesteryl ester from high-density lipoprotein for triacylglycerol in larger lipoproteins, such as very low-density lipoprotein and low-density lipoprotein. Recent trials of these agents have not shown clinical benefit. This article will review the evidence for cardiovascular risk associated with high-density lipoprotein cholesterol and discuss the implications of the trial data for cholesteryl ester transfer protein inhibitors.

    Martin Whyte, William Hinton, Andrew McGovern, Jeremy van Vlymen, Filipa Ferreira, Silvio Calderara, Julie Mount, Neil Munro, Simon de Lusignan (2019) Disparities in glycaemic control, monitoring and treatment in type 2 diabetes: a retrospective cohort analysis
    PLoS Medicine 2019; https://doi.org/10.1371/journal.pmed.1002942


    Disparities in type 2 diabetes (T2D) care provision and clinical outcomes have been reported in the last 2 decades in the UK. Since then, a number of initiatives have attempted to address this imbalance. The aim was to evaluate contemporary data as to whether disparities exist in glycaemic control, monitoring, and prescribing in people with T2D.

    Methods and findings

    A T2D cohort was identified from the Royal College of General Practitioners Research and Surveillance Centre dataset: a nationally representative sample of 164 primary care practices (general practices) across England. Diabetes healthcare provision and glucose-lowering medication use between 1 January 2012 and 31 December 2016 were studied. Healthcare provision included annual HbA1c, renal function (estimated glomerular filtration rate [eGFR]), blood pressure (BP), retinopathy, and neuropathy testing. Variables potentially associated with disparity outcomes were assessed using mixed effects logistic and linear regression, adjusted for age, sex, ethnicity, and socioeconomic status (SES) using the Index of Multiple Deprivation (IMD), and nested using random effects within general practices. Ethnicity was defined using the Office for National Statistics ethnicity categories: White, Mixed, Asian, Black, and Other (including Arab people and other groups not classified elsewhere). From the primary care adult population (n = 1,238,909), we identified a cohort of 84,452 (5.29%) adults with T2D. The mean age of people with T2D in the included cohort at 31 December 2016 was 68.7 ± 12.6 years; 21,656 (43.9%) were female. The mean body mass index was 30.7 ± SD 6.4 kg/m2. The most deprived groups (IMD quintiles 1 and 2) showed poorer HbA1c than the least deprived (IMD quintile 5). People of Black ethnicity had worse HbA1c than those of White ethnicity. Asian individuals were less likely than White individuals to be prescribed insulin (odds ratio [OR] 0.86, 95% CI 0.79–0.95; p < 0.01), sodium-glucose cotransporter-2 (SGLT2) inhibitors (OR 0.68, 95% CI 0.58–0.79; p < 0.001), and glucagon-like peptide-1 (GLP-1) agonists (OR 0.37, 95% CI 0.31–0.44; p < 0.001). Black individuals were less likely than White individuals to be prescribed SGLT2 inhibitors (OR 0.50, 95% CI 0.39–0.65; p < 0.001) and GLP-1 agonists (OR 0.45, 95% CI 0.35–0.57; p < 0.001). Individuals in IMD quintile 5 were more likely than those in the other IMD quintiles to have annual testing for HbA1c, BP, eGFR, retinopathy, and neuropathy. Black individuals were less likely than White individuals to have annual testing for HbA1c (OR 0.89, 95% CI 0.79–0.99; p = 0.04) and retinopathy (OR 0.82, 95% CI 0.70–0.96; p = 0.011). Asian individuals were more likely than White individuals to have monitoring for HbA1c (OR 1.10, 95% CI 1.01–1.20; p = 0.023) and eGFR (OR 1.09, 95% CI 1.00–1.19; p = 0.048), but less likely for retinopathy (OR 0.88, 95% CI 0.79–0.97; p = 0.01) and neuropathy (OR 0.88, 95% CI 0.80–0.97; p = 0.01). The study is limited by the nature of being observational and defined using retrospectively collected data. Disparities in diabetes care may show regional variation, which was not part of this evaluation.


    Our findings suggest that disparity in glycaemic control, diabetes-related monitoring, and prescription of newer therapies remains a challenge in diabetes care. Both SES and ethnicity were important determinants of inequality. Disparities in glycaemic control and other areas of care may lead to higher rates of complications and adverse outcomes for some groups

    M.B.Whyte, F. Shojaee-Moradie, S.E. Sharaf, D.J. Cuthbertson, G. J. Kemp, M. Barrett, N. C. Jackson, R. A. Herring, J. Wright, E.L. Thomas, J. Bell, B. Fielding, and A. M. Umpleby (2020) HDL-apoA-I kinetics in response to 16 weeks exercise training in men with non-alcoholic fatty liver disease (NAFLD)
    American Journal of Physiology 2020 June 1;318(6):E839-E847 doi: 10.1152/ajpendo.00019.2020.

    Nonalcoholic fatty liver disease (NAFLD) is characterized by low-circulating concentration of high-density lipoprotein cholesterol (HDL-C) and raised triacylglycerol (TAG). Exercise reduces hepatic fat content, improves insulin resistance and increases clearance of very-low-density lipoprotein-1 (VLDL1). However, the effect of exercise on TAG and HDL-C metabolism is unknown. We randomized male participants to 16 wk of supervised, moderate-intensity aerobic exercise (n = 15), or conventional lifestyle advice (n = 12). Apolipoprotein A-I (apoA-I) and VLDL-TAG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes (1-[13C]-leucine and 1,1,2,3,3-2H5 glycerol) pre- and postintervention. Participants underwent MRI/spectroscopy to assess changes in visceral fat. Results are means ± SD. At baseline, there were no differences between exercise and control groups for age (52.4 ± 7.5 vs. 52.8 ± 10.3 yr), body mass index (BMI: 31.6 ± 3.2 vs. 31.7 ± 3.6 kg/m2), and waist circumference (109.3 ± 7.5 vs. 110.0 ± 13.6 cm). Percentage of liver fat was 23.8 (interquartile range 9.8-32.5%). Exercise reduced body weight (101.3 ± 10.2 to 97.9 ± 12.2 kg; P < 0.001) and hepatic fat content [from 19.6%, interquartile range (IQR) 14.6-36.1% to 8.9% (4.4-17.8%); P = 0.001] and increased the fraction HDL-C concentration (measured following ultracentrifugation) and apoA-I pool size with no change in the control group. However, plasma and VLDL1-TAG concentrations and HDL-apoA-I fractional catabolic rate (FCR) and production rate (PR) did not change significantly with exercise. Both at baseline (all participants) and after exercise there was an inverse correlation between apoA-I pool size and VLDL-TAG and -apoB pool size. The modest effect of exercise on HDL metabolism may be explained by the lack of effect on plasma and VLDL1-TAG.

    Benedict McDonaugh, Martin B Whyte (2020) The evolution and future direction of cardiac biomarkers.
    EMJ Cardiol. 2020;8[1]:97-106.

    A biomarker is any measurement taken that aims to improve a diagnosis, or predict the response, to treatment of disease. Although not limited to laboratory molecular markers, this variety have attracted the most interest and seen the greatest development in recent years. The field of cardiology was an early adopter of biomarkers, with transaminases having been used for the diagnosis of acute myocardial infarction since the 1970s. The use of biomarkers has become increasingly prevalent since then and provided ever more sensitive means to diagnose myocardial cell injury or heart failure. However, diagnosis of disease at an increasingly earlier stage leads to blurring of the line between health and disease and we may be reaching the limits of early detection. Biomarkers may evolve to provide a greater understanding of the pathogenesis of cardiac disease, and by extension, the differentiation of disease subtypes. This article will review the evolution of cardiovascular biomarkers, the advantages and pitfalls associated with their use, as well as the future direction of cardiac biomarker research.

    M Stedman, M Whyte, M Lunt, M Albanese, M Livingston, R Gadsby, S Anderson, A Heald (2020) The treatment rate of erectile dysfunction (ED) in younger men with Type 2 Diabetes is up to 4 times higher than the equivalent non-diabetes population.
    Int J Clin Practice 19th May 2020 doi.org/10.1111/ijcp.13538


    Erectile Dysfunction (ED) is common in older age and in diabetes (DM). Phosphodiesterase type 5‐inhibitors (PDE5‐is) are the first‐line for ED. We investigated how type of diabetes and age of males affects the PDE5‐i use in the primary care setting.


    2018‐19 general practice level quantity of all PDE5‐i agents were taken from the GP Prescribing Data set in England. The variation in outcomes across practices was examined across one year, and for the same practice against the previous year.


    We included 5,761 larger practices supporting 25.8million men of whom 4.2million≥65 years old. Of these, 1.4million had T2DM, with 0.8million of these>65. 137,000 people had T1DM. 28.8million tablets of PDE5‐i were prescribed within the 12 months (2018‐19) period in 3.7million prescriptions (7.7 tablets/prescription), at total costs of £15.8million (£0.55/tablet).

    The NHS ED limit of 1 tablet/user/week suggests that 540,000 males are being prescribed a PDE5‐i at a cost of £29/year each. With approximately 30,000 GPs practising, this is equivalent to one GP providing 2.5 prescriptions/week to overall 18 males.

    There was a 3x variation between the highest decile of practices (2.6 tablets/male/year) and lowest decile (0.96 tablets/male/year). The statistical model captured 14% of this variation and showed T1DM males were the largest users, while men age<65 with T2DM were being prescribed 4 times as much as non‐DM. Those T2DM>65 were prescribed 80% of the non‐DM amount.


    There is wide variation in use of PDE5‐is. With only 14% variance capture, other factors including wide variation in patient awareness, prescribing rules of local health providers, and recognition of the importance of male sexual health by GP prescribers might have significant impact.

    Simon Steenson, Fariba Shojaee-Moradie, Martin B. Whyte, Kim G. Jackson, Julie L. Lovegrove, Barbara A. Fielding, A.Margot Umpleby (2020) The effect of fructose feeding on intestinal triacylglycerol production and de novo fatty acid synthesis in humans
    Nutrients 2020, 12(6), 1781; https://doi.org/10.3390/nu12061781

    A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (<2% energy) for 11 h. Oral 2H2O was administered to measure fasting and postprandial DNL. Postprandial chylomicron (CM)-TAG and very low-density lipoprotein (VLDL)-TAG kinetics were measured with an intravenous bolus of [2H5]-glycerol. CM and VLDL were separated by their apolipoprotein B content using antibodies. Plasma TAG (p < 0.005) and VLDL-TAG (p = 0.003) were greater, and CM-TAG production rate (PR, p = 0.046) and CM-TAG fractional catabolic rate (FCR, p = 0.073) lower when high-fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (p = 0.005) and apoB48 (p = 0.039), apoB100 (p = 0.013) and non-esterified fatty acids (NEFA) (p = 0.013) were higher after high-fructose. Postprandial hepatic fractional DNL was higher than intestinal fractional DNL with high-fructose (p = 0.043) and low-fructose (p = 0.043). Fructose consumption had no effect on the rate of intestinal or hepatic DNL. We provide the first measurement of the rate of intestinal DNL in humans. Lower CM-TAG PR and CM-TAG FCR with high-fructose consumption suggests lower clearance of CM, rather than elevated production, may contribute to elevated plasma TAG, possibly due to lower insulin-mediated stimulation of lipoprotein lipase

    PRJ Vas, D Hopkins, MD Feher, F Rubino, MB Whyte (2020) Diabetes, Obesity and COVID-19: A Complex Interplay
    Diabetes, Obesity and Metabolism 2020 Jul 6;10.1111/dom.14134. doi: 10.1111/dom.14134. Online ahead of print

    With the accumulation of observational data showing an association of metabolic co‐morbidities with adverse outcomes from COVID‐19, there is a need to disentangle the contributions of pre‐existing macro‐ and microvascular disease, obesity and glycaemia. This article outlines the complex mechanistic and clinical interplay between diabetes and COVID‐19, the clinical and research questions which arise from this relationship, and the types of studies needed to answer those questions. The authors are clinicians and academics working in diabetes and obesity medicine, but the article is pitched to an audience of generalists with clinical experience of or interest in the management of COVID‐19.

    Martin B. Whyte, Philip A. Kelly, Elisa Gonzalez, Roopen Arya, Lara N. Roberts (2020) Pulmonary Embolism in hospitalised patients with COVID-19
    Thrombosis Research 195 (2020): 95-99

    Background: Coronavirus disease 2019 (COVID-19) is characterised by dyspnoea and abnormal coagulation parameters, including raised D-dimer. Data suggests a high incidence of pulmonary embolism (PE) in ventilated patients with COVID-19.

    Objectives: To determine the incidence of PE in hospitalised patients with COVID-19 and the diagnostic yield of Computer Tomography Pulmonary Angiography (CTPA) for PE. We also examined the utility of D-dimer and conventional pre-test probability for diagnosis of PE in COVID-19.

    Patients/methods: Retrospective review of single-centre data of all CTPA studies in patients with suspected or confirmed COVID-19 identified from Electronic Patient Records (EPR).

    Results: There were 1477 patients admitted with COVID-19 and 214 CTPA scans performed, of which n = 180 (84%) were requested outside of critical care. The diagnostic yield for PE was 37%. The overall proportion of PE in patients with COVID-19 was 5.4%. The proportions with Wells score of ≥4 (‘PE likely’) was 33/134 (25%) without PE vs 20/80 (25%) with PE (P = 0.951). The median National Early Warning-2 (NEWS2) score (illness severity) was 5 (interquartile range [IQR] 3–9) in PE group vs 4 (IQR 2–7) in those without PE (P = 0.133). D-dimer was higher in PE (median 8000 ng/mL; IQR 4665–8000 ng/mL) than non-PE (2060 ng/mL, IQR 1210–4410 ng/mL, P < 0.001). In the ‘low probability’ group, D-dimer was higher (P < 0.001) in those with PE but had a limited role in excluding PE.

    Conclusions: Even outside of the critical care environment, PE in hospitalised patients with COVID-19 is common. Of note, approaching half of PE events were diagnosed on hospital admission. More data are needed to identify an optimal diagnostic pathway in patients with COVID-19. Randomised controlled trials of intensified thromboprophylaxis are urgently needed.

    Zixing Tan, Mike Stedman, Martin Whyte, Simon Anderson, George Thomson, Adrian Heald (2020) Personal protective equipment (PPE) and infection among healthcare workers – what is the evidence?
    International Journal of Clinical Practice 2020 Nov;74(11):e13617. doi: 10.1111/ijcp.13617. Epub 2020 Sep 9.


    The worldwide outbreak of coronavirus disease‐19 (COVID‐19) has already put healthcare workers (HCWs) at a high risk of infection. The question of how to give HCWs the best protection against infection is a priority.


    We searched systematic reviews and original studies in Medline (via Ovid) and Chinese Wan Fang digital database from inception to May, 2020, using terms 'coronavirus', 'health personnel', and 'personal protective equipment' to find evidence about the use of full‐body PPEs and other PPEs by HCW exposed highly infectious diseases.


    Covering more of the body could provide better protection for HCWs. Of importance, it is not just the provision of PPE but the skills in donning and doffing of PPE that are important, this being a key time for potential transmission of pathogen to the HCW and in due time from them to others. In relation to face masks, the evidence indicates that a higher‐level specification of face masks and respirators (such as N95) seems to be essential to protect HCWs from coronavirus infection. In community setting, the use of masks in the case of well individuals could be beneficial. Evidence specifically around PPE and protection from the COVID‐19 virus is limited.


    Covering more of the body, and a higher‐level specification of masks and respirators could provide better protection for HCWs. Community mask use could be beneficial. High quality studies still need to examine the protection of PPE against COVID‐19.

    Lara Roberts, Martin Whyte, Loizos Georgiou, Gerard Giron, Julia Czuprynska, Catherine Rea, Bipin Vadher, Raj Patel, Emma Gee, Roopen Arya (2020) Post-discharge venous thromboembolism following hospital admission with COVID-19
    Blood 2020 Aug 3;blood.2020008086. doi: 10.1182/blood.2020008086. Online ahead of print.

    The association of severe COVID-19 with an increased risk of VTE has resulted in specific guidelines for its prevention and management. The VTE risk appears highest in those with critical care admission. The need for post discharge thromboprophylaxis remains controversial and this is reflected in the conflicting recommendations of expert guidelines. Our local protocol provides thromboprophylaxis to COVID-19 patients during admission only. We report post-discharge VTE data from an ongoing quality improvement programme incorporating root cause analysis of hospital-associated VTE (HA-VTE). Following 1,877 hospital discharges associated with COVID-19, there were 9 episodes of HA-VTE diagnosed within 42 days, to give a post-discharge rate of 4.8 per 1000 discharges. Over 2019, following 18,159 discharges associated with a medical admission; there were 56 episodes of HA-VTE within 42 days (3.1 per 1000 discharges). The odds ratio for post-discharge HA-VTE associated with COVID-19 compared to 2019 was 1.6 (95% CI 0.77-3.1). Hospitalisation with COVID-19 does not appear to increase the risk of post-discharge HA-VTE compared to hospitalisation with other acute medical illness. Given the risk-benefit ratio of post discharge thromboprophylaxis remains uncertain, randomised controlled trials to evaluate the role of continuing thromboprophylaxis in patients with COVID-19 following hospital discharge are required.

    Martin B. Whyte, Prashanth Vas, Philip A. Kelly, Christian Heiss, Michael D. Feher (2020) Nitric oxide and phosphodiesterase-5 inhibitors: possible treatments for COVID-19 in diabetes
    British Journal of Diabetes 2020. https://doi.org/10.15277/bjd.2020.257

    Individuals with type 2 diabetes, hypertension and obesity have poor outcomes from coronavirus-19 (COVID-19). The presence of microvascular disease (retinopathy, microalbuminuria or neuropathy) is an independent risk factor for early death in COVID-19. Microvascular dysfunction is a systemic condition which includes pulmonary manifestations. Impaired gas transfer, due to micro- angiopathy in type 2 diabetes, suggests that individuals will be vulnerable to the pro-inflammatory state and microthrombi characteristic of ‘endothelitis’ in COVID-19. Drugs that improve blood flow in the intrapulmonary peri-alveolar microcirculation – namely, nitric oxide or phosphodiesterase-5 inhibitors – are therefore promising candidates for clinical trials in COVID-19.

    Maclean W, Limb C, Mackenzie P, Whyte M, Benton S, Rockall T, Jourdan I (2020) Adoption of Faecal Immunochemical Testing for two-week wait colorectal patients during the COVID-19 pandemic: An observational cohort study reporting a new service at a regional centre.
    Colorectal Diseases 2021 Jul;23(7):1622-1629. doi: 10.1111/codi.15408. Epub 2020 Nov 7.


    The COVID‐19 pandemic resulted in the near complete loss of routine endoscopy services. We describe a major reorganisation of service at a regional referral centre (Royal Surrey NHS Foundation Trust) to manage the crisis. Faecal immunochemical testing (FIT) was implemented for triage to make optimum use of limited diagnostic resources. Consultations were switched from face‐to‐face to telephone. We aimed to evaluate the impact FIT had on resource allocation and patient diagnoses in the first three months of use.


    All colorectal two‐week wait patient referrals were posted a pack requesting FIT and notification of telephone consultation. A pre‐paid envelope was included for return of samples. At consultation, FIT was incorporated with the presenting symptoms to guide investigation choice and triage urgency. FIT ≥10 μg/g was interpreted as positive. Outcome data was collected prospectively and compared with retrospective audit data from pre‐pandemic levels across three months.


    From 26th March 2020 to 2nd July there were 381 referrals who were invited to provide FIT samples and underwent telephone consultations. 358 FIT samples were returned (94%). Onward referral for colonoscopy reduced from 62% to 34% (p<0.001). There were fourteen colorectal cancers (3.7%) diagnosed, which was not statistically different to the pre‐pandemic level of 3.9% (p=0.995). Twelve of fourteen patients with colorectal cancer diagnoses had provided samples and all twelve had FIT ≥10 μg/g and were offered fast‐track investigations.


    Incorporation of FIT optimised the allocation of limited resources to triage those that required urgent colonic investigation in detecting colorectal cancer.

    W. Hinton, B. Nemeth, S. de Lusignan, M.D.Feher, N. Munro, L. Roberts, R. Arya, M.B.Whyte (2020) Effect of type 1 diabetes and type 2 diabetes on the risk of venous thromboembolism
    Diabetic Medicine 2020;00:e14452.


    Whether diabetes increases venous thromboembolism (VTE) is unclear. Any greater risk may relate to insulin resistance, but many studies did not differentiate between type 1 diabetes and type 2 diabetes for VTE risk.


    Retrospective cohort study of the Royal College of General Practitioners Research and Surveillance Centre, comprising over 530 primary care practices. We determined whether type 1 diabetes and/or type 2 diabetes are independent risk factors for VTE. The index date was 1st January 2009, individuals were followed to 31st December 2018, or censoring.

    Cox proportional hazard regression analysis was used to investigate the risk of VTE in people with type 1 diabetes and type 2 diabetes relative to no diabetes. The primary outcome was occurrence of VTE. The model was adjusted for potential confounders for VTE.


    There were 7,086 people with type 1 diabetes and 95,566 with type 2 diabetes, diagnosed before 1st January 2009. The non‐diabetes group consisted of 1,407,699 people. In the unadjusted analysis, there was no increased risk of VTE with type 1 diabetes (HR 1.00, 95% CI 0.76 ‐ 1.33) but there was for type 2 diabetes (HR 2.70, 95% CI 2.57 ‐ 2.84). In the fully adjusted model, VTE risk was increased in type 1 diabetes (HR 1.46, 95% CI 1.11‐1.92), but not with type 2 diabetes (HR 1.06, 95% CI 0.98‐1.14).


    Type 1 diabetes was associated with a greater risk for VTE while type 2 diabetes was not. Further work is needed to determine the reason(s) for this.

    S.J. Dauncey, P.A. Kelly, D. Baykov, A.C. Skeldon, M.B. Whyte (2021) Rhythmicity of patient flow in an acute medical unit: relationship to hospital occupancy, seven-day working, and the effect of COVID-19
    QJM 2022 Jan 5;114(11):773-779. doi: 10.1093/qjmed/hcaa334.


    The Acute Medical Unit (AMU) provides care for unscheduled hospital admissions. Seven-day Consultant presence and morning AMU discharges have been advocated to improve hospital bed management.


    To determine whether a later time of daily peak AMU occupancy correlates with measures of hospital stress; whether seven-day Consultant presence, for COVID-19, abolished weekly periodicity of discharges.


    Retrospective cohort analysis


    Anonymised AMU admission and discharge times were retrieved from the Profile Information Management System (PIMS), at a large, urban hospital from 14th April 2014—31st December 2018 and 20th March—2nd May 2020 (COVID-19 peak). Minute-by-minute admission and discharge times were combined to construct a running total of AMU bed occupancy. Fourier transforms were used to determine periodicity. We tested association between i) average AMU occupancy and ii) time of peak AMU occupancy, with measures of hospital stress (total medical bed occupancy and ‘medical outliers’ on non-medical wards).


    Daily, weekly and seasonal patterns of AMU bed occupancy were evident. Timing of AMU peak occupancy was unrelated to each measure of hospital stress: total medical inpatients (Spearman’s rho, rs=0.04, P = 0.24); number of medical outliers (rs=-0.06, P = 0.05). During COVID-19, daily bed occupancy was similar, with continuation of greater Friday and Monday discharges than the weekend.


    Timing of peak AMU occupancy did not alter with hospital stress. Efforts to increase morning AMU discharges are likely to have little effect on hospital performance. Seven-day Consultant presence did not abolish weekly periodicity of discharges – other factors influence weekend discharges.

    Heald AH, Stedman M, Whyte M, Livingston M, Albanese M, Ramachandran S, G Hackett (2021) Lessons learnt from the variation across 6741 family/general practices in England in the use of treatments for hypogonadism
    Clinical Endocrinology Jan 8th 2021 doi: 10.1111/cen.14412.


    We have previously reported rates of diagnosis of male hypogonadism in United Kingdom (UK) general practices. We aimed to identify factors associated with testosterone prescribing in UK general practice.


    We determined for 6741 general practices in England, the level of testosterone prescribing in men and the relation between volume of testosterone prescribing and (1) demographic characteristics of the practice, (2) % patients with specific comorbidities and (3) national GP patient survey results.


    The largest volume (by prescribing volume) agents were injectable preparations at a total cost in the 12‐month period 2018/19 of £8,172,519 with gel preparations in second place: total cost £4,795,057. Transdermal patches, once the only alternative to testosterone injections or implants, were little prescribed: total cost £222,022. The analysis accounted for 0.27 of the variance in testosterone prescribing between general practices. Thus, most of this variance was not accounted for by the analysis. There was a strong univariant relation (r = .95, P < .001) between PDE5‐I prescribing and testosterone prescribing. Other multivariant factors independently linked with more testosterone prescribing were as follows: HIGHER proportion of men with type 2 diabetes(T2DM) on target control (HbA1c ≤ 58 mmol/mol) and HIGHER overall practice rating on the National Patient Survey for good experience, while non‐white ethnicity and socio‐economic deprivation were associated with less testosterone prescribing. There were a number of comorbidity factors associated with less prescribing of testosterone (such as T2DM, hypertension and stroke/TIA).


    Our analysis has indicated that variation between general practices in testosterone prescribing in a well developed health economy is only related to small degree (r2 = 0.27) to factors that we can define. This suggests that variation in amount of testosterone prescribed is largely related to general practitioner choice/other factors not studied and may be amenable to measures to increase knowledge/awareness of male hypogonadism, with implications for men's health.

    Martin B. Whyte, Rosemary Barker, Philip A. Kelly, Elisa Gonzalez, Julia Czuprynska, Raj K. Patel, Catherine Rea, Caroline Jolley, Roopen Arya, Lara N. Roberts (2021) Three-month follow-up of VTE in patients with COVID-19
    Thrombosis Research. 2021 May; 201: 113–115.
    S Ramachandran, RW Foley, A Akintimehin, S Williams, SJ Connor, J Hart, YK Kapadia, I Timofeev, CM Tolias, MB Whyte, PA Kelly (2021) Subarachnoid Hemorrhage Rules in the Decision For Acute CT Head: External Validation in a Multi-institutional UK Cohort
    Clinical Medicine 2021;21(2):96-100. doi: 10.7861/clinmed.2020-0437.

    Background: The Ottawa subarachnoid haemorrhage (SAH) rule and the Emerald SAH rule are clinical decision tools to aid in the decision for computed tomography (CT) of the head in patients attending an emergency department (ED) with acute non-traumatic headache. The objective of this study was to analyse the performance of these rules in a contemporary UK cohort.

    Methods: We performed a retrospective external validation study. Patients undergoing CT of the head for the evaluation and treatment of non-traumatic headaches over a 6-month period in the ED at two tertiary centres were assessed. Each patient's Ottawa rule and Emerald rule were calculated and compared with their final diagnosis.

    Results: The cohort consisted of 366 patients and there were 16 cases of SAH (based on CT findings or the presence of xanthochromia in cerebrospinal fluid). The Ottawa rule identified 288 patients requiring CT of the head. The sensitivity of the Ottawa rule was 100% (95% confidence interval (CI) 71-100%) and the specificity was 22% (95% CI 18-27%). The Emerald rule identified 267 patients who required CT, and achieved a sensitivity of 81% (95% CI 54-96%) and a specificity of 27% (95% CI 23-32%).

    Conclusions: The Ottawa SAH rule correctly identified all patients with SAH in this contemporary cohort. The Emerald rule did not perform as well in this cohort and is unsuitable for clinical use. The Ottawa rule is a useful tool to aid in the decision for CT of the head in patients presenting with acute non-traumatic headache to the ED.

    Savan Shah, Michael Feher, Andrew McGovern, Martin B Whyte, Neil Munro, William Hinton, Piers Gatenby, Simon de Lusignan (2021) Retinopathy in newly diagnosed Type 2 diabetes: prevalence and predictors of progression; A national primary network study
    Diabetes Research and Clinical Practice 2021 May;175:108776. doi: 10.1016/j.diabres.2021.108776.


    To determine, in real-world primary care settings, the prevalence of, and risk factors for, retinopathy at Type 2 diabetes mellitus diagnosis and report cumulative incidence and progression of retinopathy seven years after diabetes diagnosis.


    Retrospective cohort analysis of people with newly diagnosed Type 2 diabetes recorded by the Royal College of General Practitioners Research and Surveillance Centre (between 2005-2009, n=11,399). Outcomes included; retinopathy prevalence at diabetes diagnosis (baseline) and cumulative incidence or progression of retinopathy at seven years. Retinopathy prevalence was compared with the United Kingdom Prospective Diabetes Study (UKPDS-1998). Factors influencing retinopathy incidence and progression were analysed using logistic regression.


    Baseline retinopathy prevalence was 18% (n=2,048) versus 37% in UKPDS. At seven years, 11.6% (n=237) of those with baseline retinopathy had progression of retinopathy. In those without baseline retinopathy, 46.4% (n=4,337/9,351) developed retinopathy by seven years. Retinopathy development (OR:1.05 [95%CI:1.02-1.07] per mmol/mol increase) and progression (OR:1.05[1.04–1.06]) at seven years was associated with higher HbA1c at diabetes diagnosis. Obesity (OR:0.88[0.79–0.98]) and high socioeconomic status (OR:0.63[0.53-0.74]) were negatively associated with retinopathy development at seven years.


    Baseline retinopathy prevalence has declined since UKPDS. Additionally, HbA1c at diabetes diagnosis remains important for retinopathy development and progression.

    Martin B. Whyte, Prash Vas, Margot Umpleby (2021) Could exogenous insulin ameliorate the metabolic dysfunction induced by glucocorticoids and COVID-19?
    Frontiers in Endocrinology 2021 doi: 10.3389/fendo.2021.649405

    The finding that high-dose dexamethasone improves survival in those requiring critical care due to COVID-19 will mean much greater usage of glucocorticoids in the subsequent waves of coronavirus infection. Furthermore, the consistent finding of adverse outcomes from COVID-19 in individuals with obesity, hypertension and diabetes has focussed attention on the metabolic dysfunction that may arise with critical illness. The SARS coronavirus itself may promote relative insulin deficiency, ketogenesis and hyperglycaemia in susceptible individuals. In conjunction with prolonged critical care, these components will promote a catabolic state. Insulin infusion is the mainstay of therapy for treatment of hyperglycaemia in acute illness but what is the effect of insulin on the admixture of glucocorticoids and COVID-19?
    This article reviews the evidence for the effect of insulin on clinical outcomes and intermediary metabolism in critical illness.

    Maclean W, Mackenzie P, Limb C, Whyte MB, Zahoor, Z, Rockall T, Benton S, Jourdan I (2021) Diagnostic accuracy of point of care faecal immunochemical testing using a portable high-speed quantitative analyser for diagnosis in 2-week wait patients.
    Colorectal Diseases. 2021 Jun 22. doi: 10.1111/codi.15780

    Aim: Laboratory-based faecal immunochemical testing (FIT) is the gold standard for detecting the presence of blood in the stool. The aim was to perform a diagnostic accuracy study to confirm if a point of care (POC) analyser for FIT could be safely used as an adjunct in the triage and management of 2-week wait (TWW) colorectal patients.

    Methods: The Point of Care Faecal Immunochemical Testing (POC FIT) prospective observational cohort study was designed for TWW patients at a regional referral centre. Between July 2019 and March 2020, patients were invited to perform and bring a FIT sample to clinic. FIT was completed within the clinic appointment using a POC quantitative analyser that has a 2-min processing time (QuikRead go®). Patients and clinicians were blinded to results within the clinic appointment. The results were compared with subsequent diagnostic outcomes. Faecal haemoglobin of <10 µg haemoglobin/g of faeces was considered a negative result. Sensitivities for colorectal cancer (CRC) and combined serious bowel disease (SBD) were calculated using this pre-determined cut-off.

    Results: A total of 553 patients were included for analytical comparison with diagnostic outcomes. There were 14 (2.5%) patients with CRC and 52 (9.4%) with SBD. The sensitivities for CRC and SBD were 92.9% (95% CI 68.5%-98.7%) and 76.9% (95% CI 63.9%-86.3%) respectively. 379 (68.5%) patients had a negative FIT result (negative predictive value for CRC was 99.7%).

    Conclusions: This POC FIT device is a useful adjunct to better manage TWW patients. The high observed sensitivity for CRC offers opportunities, within a single consultation, for improved triage and rationalization of investigation for those with bowel symptoms.

    Adrian Heald, Rustam Rea, Linda Horne, Ann Metters, Tom Steele, Kathryn Leivesley, Martin Whyte, Mike Stedman, Bill Ollier (2021) Analysis of continuous glucose tracking data in people with Type 1 Diabetes (T1DM) after Covid-19 Vaccination reveals unexpected link between immune and metabolic response, augmented by adjunctive oral medication.
    Int J Clin Practice 2021. Aug 2021 https://doi.org/10.1111/ijcp.14714

    Introduction: The COVID-19 vaccination programme is under way worldwide. Anecdotal evidence is increasing that some people with Type 1 Diabetes Mellitus (T1DM) experience temporary instability of blood glucose (BG) levels post-vaccination which normally settles within 2-3 days. We report an analysis of BG profiles of 20 individuals before/after vaccination.

    Methods: We examined the BG profile of 20 consecutive adults (18 years of age or more) with T1DM using the FreeStyle® Libre flash glucose monitor in the period immediately before and after COVID-19 vaccination. The primary outcome measure was percentage (%) BG readings in the designated target range 3.9-10mmmol/L as reported on the LibreView portal for 7 days prior to the vaccination (week -1) and the 7 days after the vaccination (week +1).

    Results: There was a significant decrease in the %BG on target following the COVID-vaccination for the 7 days following vaccination (mean 45.2% ±se 4.2%) vs pre-COVID-19 vaccination (mean 52.6% ±se 4.5%). This was mirrored by an increase in the proportion of readings in other BG categories 10.1-13.9%/ ≥14%. There was no significant change in BG variability in the 7days post COVID-19 vaccination. This change in BG proportion on target in the week following vaccination was most pronounced for people taking Metformin/Dapagliflozin+basal bolus insulin (-23%) vs no oral hypoglycaemic agents (-4%), and median age <53 vs ≥53 years (greater reduction in %BG in target for older individuals (-18% vs -9%)).

    Conclusion: In T1DM, we have shown that COVID-19 vaccination can cause temporary perturbation of BG, with this effect more pronounced in patients talking oral hypoglycaemic medication plus insulin, and in older individuals. This may also have consequences for patients with T2DM who are currently not supported by flash glucose monitoring.

    Reuben M Reed, Sarah J Nevitt, Graham J Kemp, Daniel J Cuthbertson, Martin B Whyte, Louise M Goff (2021) Ectopic fat deposition in populations of black African ancestry compared with other ethnicities: A systematic review.
    Acta Diabetologica Sept 2021. doi: 10.1007/s00592-021-01797-5

    Aims: In populations of black African ancestry (BA), a paradox exists whereby lower visceral adipose tissue is found despite their high risk for type 2 diabetes (T2D). This systematic review investigates ethnic differences in other ectopic fat depots (intrahepatic lipid: IHL; intramyocellular lipid: IMCL and intrapancreatic lipid; IPL) to help contextualise their potential contribution to T2D risk.

    Methods: A systematic literature search was performed in December 2020 to identify studies reporting at least one ectopic fat comparison between BA and one/more other ethnicity. For IHL, a meta-analysis was carried out with studies considered comparable based on the method of measurement.

    Results: Twenty-eight studies were included (IHL: n = 20; IMCL: n = 8; IPL: n = 4). Meta-analysis of 11 studies investigating IHL revealed that it was lower in BA populations vs pooled ethnic comparators (MD -1.35%, 95% CI -1.55 to -1.16, I2 = 85%, P < 0.00001), white European ancestry (MD -0.94%, 95% CI -1.17 to -0.70, I2 = 79%, P < 0.00001), Hispanic ancestry (MD -2.06%, 95% CI -2.49 to -1.63, I2 = 81%, P < 0.00001) and South Asian ancestry comparators (MD -1.92%, 95% CI -3.26 to -0.57, I2 = 78%, P = 0.005). However, heterogeneity was high in all analyses. Most studies found no significant differences in IMCL between BA and WE. Few studies investigated IPL, however, indicated that IPL is lower in BA compared to WE and HIS.

    Conclusion: The discordance between ectopic fat and greater risk for T2D in BA populations raises questions around its contribution to T2D pathophysiology in BA.

    Marc Evans, Ruth D. Lewis, Angharad R. Morgan, Martin B. Whyte, Wasim Hanif, Stephen C. Bain, Sarah Davies, Umesh Dashora, Zaheer Yousef, Philip A. Kalra, Dipesh C. Patel, William D. Strain. David C. Wheeler. (2021) A narrative review of CKD in clinical practice: Current challenges and future perspectives
    Advances in Therapy 2021; Nov 5; 1-11 doi: 10.1007/s12325-021-01927-z.

    Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world's population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and the unmet patient need in CKD.

    Adrian Li, Martin B Whyte (2021) Disparities in Diabetes Care
    EMJ Diabet. 2021;9[1]:92-101

    Disparities in the distribution of diabetes health have been reported by social class, age, gender, and ethnicity and may arise from an interplay of biological, clinical, and non-clinical factors. As well as being morally wrong, these differences in outcome will have a significant adverse effect on a nation’s health. As a result, there have been international efforts to reduce inequalities, from the strategic organisation of healthcare to providers and patients themselves, with mixed effects. This article outlines the disparities in diabetes care and outcomes in different patient groups, and how the approach of integration of health and social care may help to overcome some of the adverse aspects of societal organisation that underpins disparities.

    William Maclean, Zahida Zahoor, Shane O'Driscoll, Carolyn Piggott, Martin B. Whyte, Timothy Rockall, Iain Jourdan, Sally C. Benton (2021) Comparison of the QuikRead Go point-of-care faecal immunochemical test for haemoglobin with the FOB Gold Wide laboratory analyser to diagnose colorectal cancer in symptomatic patients
    Clin Chem Lab Med Oct 2021 https://doi.org/10.1515/cclm-2021-0655


    Faecal immunochemical testing for haemoglobin (FIT) is used to triage patients for colonic investigations. Point-of-care (POC) FIT devices on the market have limited data for their diagnostic accuracy for colorectal cancer (CRC). Here, a POC FIT device is compared with a laboratory-based FIT system using patient collected samples from the urgent referral pathway for suspected CRC.


    A prospective, observational cohort study. Patients collected two samples from the same stool. These were measured by POC QuikRead go® (Aidian Oy, Espoo, Finland) and laboratory-based FOB Gold Wide® (Sentinel Diagnostics, Italy). Faecal haemoglobin <10 μg haemoglobin/g of faeces was considered as negative. At this threshold, comparisons between the two systems were made by calculating percentage agreement and Cohen’s kappa coefficient. Proportion of negative results were compared with Chi squared testing. Sensitivities for CRC were calculated.


    A total of 629 included patients provided paired samples for FIT to compare the QuikRead go® and FOB Gold Wide®. The agreement around the negative threshold was 83.0% and Cohen’s kappa coefficient was 0.54. The QuikRead go® reported 440/629 (70.0% of samples) as negative compared to 523/629 (83.1%) for the FOB Gold Wide®, this difference was significant (p-value<0.001). Sensitivities for CRC detection by the QuikRead go® and FOB Gold Wide® were 92.9% (95% confidence interval (CI): 68.5–98.7%) and 100% (CI: 78.5–100%) respectively.


    Both systems were accurate in their ability to detect CRC. Whilst good agreement around the negative threshold was identified, more patients would be triaged to further colonic investigation if using the QuikRead go®.

    Marc Evans, Angharad R. Morgan, Martin B. Whyte, Wasim Hanif, Stephen C. Bain, Philip A. Kalra, Sarah Davies, Umesh Dashora, Zaheer Yousef, Dipesh C. Patel, William D. Strain. David C. Wheeler (2021) New therapeutic horizons in CKD: A consensus viewpoint on the role of SGLT2 inhibitors in clinical practice.
    Drugs 2021 Dec 21. doi: 10.1007/s40265-021-01655-2. Online ahead of print.

    Chronic kidney disease (CKD) is a serious, progressive condition associated with significant patient morbidity. Hypertension control and use of renin-angiotensin system blockers are the cornerstones of treatment for CKD. However, even with these treatment strategies, many individuals will progress towards kidney failure. Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitor clinical trials with primary renal endpoints have firmly established SGLT2 inhibition, in addition to standard of care, as an effective strategy to slow down the progression of CKD and reduce some of its associated complications. The emergence of this new clinical evidence supports the use of SGLT2 inhibitors in the management of CKD in people with and without diabetes. As licensing and guidelines for SGLT2 inhibitors are updated, there is a need to adapt CKD treatment pathways and for this class of drugs to be included as part of standard care for CKD management. In this article, we have used consensus opinion alongside the available evidence to provide support for the healthcare community involved in CKD management, regarding the role of SGLT2 inhibitors in clinical practice. By highlighting appropriate prescribing and practical considerations, we aim to encourage greater and safe use of SGLT2 inhibitors for people with CKD, both with and without diabetes.

    Ruman Basra, Martin Whyte, Janaka Karalliedde, Prashanth Vas (2022) What is the impact of micro vascular complications of diabetes on severe Covid-19?
    Microvascular Research Volume 140, March 2022, 104310

    Evidence suggests severe coronavirus disease-19 (COVID-19) infection is characterised by pulmonary and systemic microvasculature dysfunction, specifically, acute endothelial injury, hypercoagulation and increased capillary permeability. Diabetes, which is also characterised by vascular injury in itself, confers an increased risk of adverse COVID-19 outcomes. It has been suggested that pre-existing endothelial dysfunction and microvascular disease in diabetes will exacerbate the vascular insults associated with COVID-19 and thus lead to increased severity of COVID-19 infection. In this article, we evaluate the current evidence exploring the impact of microvascular complications, in the form of diabetic retinopathy and nephropathy, in individuals with COVID-19 and diabetes. Future insights gained from exploring the microvascular injury patterns and clinical outcomes may come to influence care delivery algorithms for either of these conditions.

    A.H Heald, M. Stedman, L. Horne, R. Rea, M.B. Whyte, J.M. Gibson, M.Livingston, S.G. Anderson, W. Ollier (2021) The change in glycaemic control immediately after COVID-19 vaccination in people with type 1 diabetes.
    Diabetic Medicine; Online 30th Dec 2021 doi.org/10.1111/dme.14774


    Evidence suggests that some people with type 1 diabetes mellitus (T1DM) experience temporary instability of blood glucose (BG) levels after COVID-19 vaccination. We aimed to assess this objectively.


    We examined the interstitial glucose profile of 97 consecutive adults (age ≥ 18 years) with T1DM using the FreeStyle Libre® flash glucose monitor in the periods immediately before and after their first COVID-19 vaccination. The primary outcome measure was percentage (%) interstitial glucose readings within the target range 3.9–10 mmol/L for 7 days prior to the vaccination and the 7 days after the vaccination. Data are mean ± standard error.


    There was a significant decrease in the % interstitial glucose on target (3.9–10.0) for the 7 days following vaccination (mean 52.2% ± 2.0%) versus pre-COVID-19 vaccination (mean 55.0% ± 2.0%) (p = 0.030). 58% of individuals with T1DM showed a reduction in the 'time in target range' in the week after vaccination. 30% showed a decrease of time within the target range of over 10%, and 10% showed a decrease in time within target range of over 20%. The change in interstitial glucose proportion on target in the week following vaccination was most pronounced for people taking metformin/dapagliflozin + basal bolus insulin (change −7.6%) and for people with HbA1c below the median (change −5.7%).


    In T1DM, we have shown that initial COVID-19 vaccination can cause temporary perturbation of interstitial glucose, with this effect more pronounced in people talking oral hypoglycaemic medication plus insulin, and when HbA1c is lower.

    Adrian Heald; Michael Stedman; Adam Robinson; Mark Davies; Mark Livingston; Ramadan Alshames; Gabriela Cortes; Roger Gadsby; Gerry Rayman; John Martin Gibson; Simon de Lusignan; Martin Whyte (2022) Mortality Rate Associated with Diabetes: Outcomes From a General Practice Level analysis in England Using the Royal College of General Practitioners (RCGP) Database Indicate Stability Over a 15 Year Period.
    Diabetes Therapy 2022 2022 Mar;13(3):505-516. doi: 10.1007/s13300-022-01215-1. Epub 2022 Feb 21.

    Introduction: Total population mortality rates have been falling and life expectancy increasing for more than 30 years. Diabetes remains a significant risk factor for premature death. Here we used the Oxford Royal College of General Practitioners Research and Surveillance Centre (RCGP RSC) practices to determine diabetes-related vs non-diabetes-related mortality rates.

    Methods: RCGP RSC data were provided on annual patient numbers and deaths, at practice level, for those with and without diabetes across four age groups (< 50, 50-64, 65-79, ≥ 80 years) over 15 years. Investment in diabetes control, as measured by the cost of primary care medication, was also taken from GP prescribing data.

    Results: We included 527 general practices. Over the period 2004-2019, there was no significant change in life years lost, which varied between 4.6 and 5.1 years over this period. The proportion of all diabetes deaths by age band was significantly higher in the 65-79 years age group for men and women with diabetes than for their non-diabetic counterparts. For the year 2019, 26.6% of deaths were of people with diabetes. Of this 26.6%, 18.5% would be expected from age group and non-diabetes status, while the other 8.1% would not have been expected-pro rata to nation, this approximates to approximately 40,000 excess deaths in people with diabetes vs the general population.

    Conclusion: There remains a wide variation in mortality rate of people with diabetes between general practices in UK. The mortality rate and life years lost for people with diabetes vs non-diabetes individuals have remained stable in recent years, while mortality rates for the general population have fallen. Investment in diabetes management at a local and national level is enabling us to hold the ground regarding the life-shortening consequences of having diabetes as increasing numbers of people develop T2DM at a younger age.

    Maclean W, Whyte MB, Benton S, Rockall T, Jourdan I (2022) Patient reported outcome measures to show FIT as an acceptable investigation to rule out colorectal cancer in the two-week wait cohort.
    Annals of Royal College of Surgeons 2022 doi.org/10.1308/rcsann.2022.0025

    Introduction: Use of faecal immunochemical testing (FIT) for symptomatic patients is increasing. FIT is recommended as a triage tool from primary care to the two-week wait (TWW) suspected cancer pathway, but there is still little known about patient attitudes.

    Aim: The aim of this study was to explore patient opinions of FIT and how it might be applied in the TWW pathway.

    Methods: A telephone survey was conducted for patients from the TWW pathway who had undergone both conventional colonic investigation and FIT. Five questions explored expectations, attitudes towards results and experience of the investigations using a Likert scale 1-5. Differences in opinion were compared using median and mode scores and visualised using bar charts.

    Results: One hundred and nine TWW patients agreed to answer the five questions. All had taken a stool sample for FIT, 50 underwent colonoscopy, 51 had a CT colonography and 8 underwent flexible sigmoidoscopy. Most patients (85%) scored 5 (completely satisfied) with these conventional colonic investigation methods they underwent for ruling out colorectal cancer (median 5). However, 30% of patients scored 5 (completely satisfied) if using a negative FIT to not require additional colonic investigation. The median score to perform FIT was 5 (very easy) compared with a median of 4 (easy) to undergo the other colonic investigations.

    Conclusions: Symptomatic patients can perform FIT with little difficulty, and often would have been happy to avoid conventional colonic investigations with a negative result. However, shared decision-making should be employed to identify those who would be dissatisfied with relying on FIT for further investigation decisions.

    A.Surendran, A.Bhalla, MB.Whyte (2022) Improved diabetes control, allowing insulin cessation, after direct acting antiviral treatment (DAAT) of Hepatitis C
    BMJ Case Reports 2022;15:4

    There is a bidirectional relationship between hepatitis C and type 2 diabetes. The risk for developing type 2 diabetes is increased in patients with chronic hepatitis C virus (HCV) infection—with the prevalence of diabetes ranging from 13% to 33%. This is likely underpinned by insulin resistance. Type 2 diabetes may also be a predisposing factor for HCV infection. The new non-interferon-based therapeutic regimens for hepatitis C have transformed care and can eradicate disease. In this report, we show how such a regimen eradicated viral load, improved hepatocellular blood markers and significantly improved dysglycaemia, such that all glucose-lowering medication could be stopped.

    Martin Whyte, Mark Joy, William Hinton, Andrew McGovern, Uy Hoang, Jeremy van Vlymen, Filipa Ferreira, Julie Mount, Neil Munro, Simon de Lusignan (2022) Early and ongoing stable glycaemic control is associated with a reduction in major adverse cardiovascular events (MACE) in people with type 2 diabetes: primary care cohort study.
    Diabetes, Obesity, Metabolism 2022 Jul;24(7):1310-1318. doi: 10.1111/dom.14705. Epub 2022 Apr 18.


    To determine whether achieving early glycaemic control, and any subsequent glycaemic variability, was associated with any change in risk of major adverse cardiovascular events (MACE).

    Materials and Methods

    A retrospective cohort analysis from the Oxford-Royal College of General Practitioners Research and Surveillance Centre database - a large, English primary care network. We followed newly diagnosed patients with type 2 diabetes, on or after 1st Jan 2005, aged ≥25 years at diagnosis, with an HbA1c measure at both diagnosis and 1-year; plus ≥5 measurements of HbA1c thereafter.

    Three glycaemic bands were created; A (HbA1c <58 mmol/mol, 7.5%), B (HbA1c ≥58 to 75 mmol/mol, 7.5–9.0%) and C (HbA1c ≥75 mmol/mol, 9.0%). Movement between bands was determined from diagnosis to 1-year. Additionally, for data after the first 12-months, a glycaemic variability score was calculated from the number of successive HbA1c readings differing by ≥0·5% (5·5 mmol/mol). Risk of MACE from 1-year post-diagnosis was assessed using time-varying Cox proportional hazards models, that included the first-year transition and the glycaemic variability score.


    From 26,180 patients, there were 2,300 MACE. Compared to Group A->A transition over 1-year, those with C->A transition had reduced risk of MACE (HR 0.75; 95% CI 0.60 – 0.94; P=0.014) whereas C->C had HR 1.21 (0.81 – 1.81; P=0.34). Compared to lowest glycaemic variability score, greatest variability increased risk for MACE (HR 1.51; 1.11 – 2.06; P=0.0096).


    Early control of glycated haemoglobin improved cardiovascular outcomes in type 2 diabetes, though subsequent glycaemic variability had a negative effect on an individual's risk.

    Martin B Whyte and Philip A Kelly (2022) The effect of the electronic health record on consultants' responsibility for patients and their care in general medicine.
    Future Healthcare Journal May 2022. DOI: https://doi.org/10.7861/fhj.2022-0001

    The electronic health record has dramatically improved the safety of medical care as well as the clarity and accessibility of the notes. An equally profound, but under-recognised consequence, is the effect it has had on ‘patient ownership' and responsibility within the hospital. It is now very easy to access and read through patients notes, from a distance and at scale, to identify patients for attention. Automated alerts can be set for quantitative laboratory or physiological variables, for the same purpose, and artificial intelligence is being developed for alerts based on free text or radiographic interpretation. This article explores the risk of this approach to healthcare and the danger of a ‘collusion of anonymity', whereby responsibility for care is sufficiently diffuse that no one has ownership of a patient's care.

    Andrew McGovern, William Hinton, Emmanouela Konstantara, Neil Munro, Emily Williams, Ben Field, Martin Whyte, Julie Mount, Michael Feher, Simon de Lusignan (2022) Intensification to injectable therapy in type 2 diabetes: mixed methods study
    Diabetes Therapy 2022 Sep 2. doi: 10.1007/s13300-022-01306-z. Online ahead of print

    Background: In the UK, type 2 diabetes mellitus (T2D) is largely managed in primary care. Delay in the intensification to injectable therapy, a form of clinical inertia, is associated with worse glycaemic control. UK general practice is highly computerised, with care being recorded on computerised medical record systems; this allows for quantitative analysis of clinical care but not of the underpinning decision-making process. The aim of this study is to investigate perceptions of patients and clinicians in primary care on the initiation of injectable therapies in T2D, and the context within which those decisions are made.

    Methods: This is a mixed methods study, taking a "realist evaluation" approach. The qualitative components comprise focus groups, interviews, and video recordings of simulated surgeries; the quantitative analysis: an overview of participating practices, elements of the video recording, and an online survey. We will recruit primary care clinicians (general practitioners and nurses) and patients from a representative sample of practices within the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network. Participants will be patients with T2D, and primary care clinicians. Focus groups and semi-structured interviews will be recorded, transcribed verbatim and analysed using Framework Analysis. The simulated surgeries will include cases that might be escalated to injectable therapy. The consultation will be reviewed using the Calgary-Cambridge model to assess communication and determination of adherence to national prescribing guidelines. We will conduct multi-channel video recording including screen capture, clinician and patient facial expressions, wide angle view of the consultation, and the computerised medical record screen. This allows annotation and qualitative analysis of the video recordings, and statistical analyses for the quantitative data. We will also conduct an online survey of primary care clinicians' attitudes to, and perceptions of, initiation of injectable therapies, which will be analysed using summary statistics.

    Discussion: Results aim to provide a detailed insight into the dynamic two-way decision-making process underpinning use of injectable therapy for T2D. The study will provide insights into clinical practice and enable the development of training, interventions and guidelines that may facilitate, where appropriate, the intensification to injectable therapy.

    Morgan Jervis, Antonine Pineau Mitchell, Nafseen Islam, Omar G. Mustafa, Philip A. Kelly, Martin B. Whyte (2022) GLP-1 receptor agonist use during hospitalisation: better glycaemic control compared to pre-mixed insulin.
    Diabetes/Metabolism Research & Reviews 2022: Nov;38(8):e3574


    Glycaemic control associates with better outcomes for hospitalised patients. Whether GLP-1 receptor agonists (GLP-1 RA) are suitable and effective drugs for inpatients is unclear.


    A retrospective, single centre, observational study using data from the Electronic Health Record. Patients admitted using GLP-1 RA as outpatients, from 2016 to 2019, were identified. Outcomes were compared to those admitted using twice daily (BD) mixed insulin. Capillary glucose, medication use, creatinine and demographic data were collected. As drugs may be discontinued/not administered in hospital, days when GLP-1 RA was administered were ‘GLP-1 RA active’ and, for insulin, ‘insulin active’. The primary comparison was rate of hypoglycaemia (<4mmol/L) and severe hypoglycaemia (<3 mmol/L). A logistic regression model examined variables for hypoglycaemia.


    GLP-1 RA comprised n=262 admissions and BD insulin n=166. The ‘insulin active’ cohort (n=957 patient days) had higher risk of hypoglycaemia than ‘GLP-1 RA active’ (n=806 days); occurring on 14.7% of days; 95% confidence interval [CI] 12.6–17.1 vs 9.9% days; 95% CI 8.0-12.2; P=0.002), and severe hypoglycaemia 4.0% of days (95% CI 2.8–5.4) vs 2.0% (95% CI 1.1–3.2%; P=0.005). Daily glucose (mean ± standard deviation) was 10.8±5.2 mmol/L in insulin active vs 9.6±4.7 mmol/L in GLP-1 RA active; P<0.001. Insulin use, age and acute admissions predicted hypoglycaemia. Odds ratio for hypoglycaemia was 2.15 times greater (95% CI, 1.14-4.08; P=0.019) with insulin than GLP-1 RA.


    GLP-1 RA provided better glycaemic control than BD mixed insulin and should be continued during hospitalisation unless a clear indication for cessation.

    M.B.Whyte, A.Heald, B.C.T. Field (2022) Harnessing the incretin system with multi-agonists
    EMJ Innov. 2022; DOI/10.33590/emjinnov/10115628.

    The scientific community has made great strides in responding to the huge public health problems of obesity and diabetes with the discovery of the incretin system and the development of glucagon-like peptide 1 analogues. These have shown clinical efficacy in randomised controlled trials and observational data from real-world evidence; however, a ‘treatment gap’ remains between the therapeutic success of these molecules and the outcomes achieved with bariatric surgery. To help address this, dual incretins are being developed. These combine glucagon-like peptide 1 action with that of either glucose-dependent insulinotropic peptide or glucagon. This narrative review charts the development of incretin therapy, and the dual agonists for treatment of Type 2 diabetes and obesity.

    Mariam Bapir, Gavrielle R. Untracht, Debbie Cooke, John H. McVey, Simon S. Skene, Paola Campagnolo, Martin B. Whyte, Nikolaos Dikaios, Ana Rodriguez-Mateos, David D. Sampson, Danuta M. Sampson, Christian Heiss (2022) Cocoa flavanol consumption improves lower extremity endothelial function in healthy individuals and people with type 2 diabetes
    Food and Function 2022 Sept 20th https://doi.org/10.1039/D2FO02017C

    Background: Diabetes and age are major risk factors for the development of lower extremity peripheral artery disease (PAD). Cocoa flavanol (CF) consumption is associated with lower risk for PAD and improves brachial artery (BA) endothelial function. Objectives: To assess if femoral artery (FA) endothelial function and dermal microcirculation are impaired in individuals with type 2 diabetes mellitus (T2DM) and evaluate the acute effect of CF consumption on FA endothelial function.

    Methods: In a randomised, controlled, double-blind, cross-over study, 22 individuals (n=11 healthy, n=11 T2DM) without cardiovascular disease were recruited. Participants received either 1,350 mg CF or placebo capsules on 2 separate days in random order. Endothelial function was measured as flow-mediated dilation (FMD) using ultrasound of the common FA and the BA before and 2 hours after interventions. The cutaneous microvasculature was assessed using optical coherence tomography angiography.

    Results: Baseline FA-FMD and BA-FMD were significantly lower in T2DM (FA: 3.2±1.1%[SD], BA: 4.8±0.8%) compared to healthy (FA: 5.5±0.7%, BA: 6.0±0.8%); each p<0.001. Whereas in healthy individuals FA-FMD did not significantly differ from BA-FMD (p=0.144), FA-FMD was significantly lower than BA-FMD in T2DM (p=0.003) indicating pronounced and additional endothelial dysfunction of lower limb arteries (FA-FMD/BA-FMD: 94±14% [healthy] vs 68±22% [T2DM], p=0.007). The baseline FA blood flow rate (0.42±0.23 vs 0.73±0.35 l/min, p=0.037) and microvascular dilation in response to occlusion in hands and feet were significantly lower in T2DM subjects than in healthy ones. CF increased both FA- and BA-FMD at 2 hours, compared to placebo, in both healthy and T2DM subgroups (FA-FMD effect: 2.9±1.4%, BA-FMD effect 3.0±3.5%, each pintervention<0.001). In parallel, baseline FA blood flow and microvascular diameter increased in feet (3.5±3.5 um, pintervention<0.001) but not hands. Systolic blood pressure and pulse wave velocity decreased after CF in both subgroups (-7.2±9.6 mmHg, pintervention=0.004; -1.3±1.3 m/s, pintervention=0.002).

    Conclusions: Individuals with T2DM exhibit decreased endothelial function that is more pronounced in the femoral than in the brachial artery. CFs increase endothelial function not only in the BA but also the FA both in healthy individuals and in those with T2DM who are at increased risk of developing lower extremity PAD and foot ulcers.

    Agnieszka Lemanska, Claire Price, Nathan Jeffreys, Rachel Byford, Hajira Dambha-Miller, Xuejuan Fan, William Hinton, Sophie Otter, Rebecca Rice, Julian Sherlock, Ali Stunt, Martin B. Whyte, Sara Faithfull, Simon de Lusignan (2022) BMI and HbA1c are metabolic markers for pancreatic cancer: a matched case-control study using a UK primary care database.
    PLoS ONE 2022 Oct 5th doi.org/10.1371/journal.pone.0275369


    Weight loss, hyperglycaemia and diabetes are known features of pancreatic cancer. We quantified the timing and the amount of changes in body mass index (BMI) and glycated haemoglobin (HbA1c), and their association with pancreatic cancer from five years before diagnosis.



    A matched case-control study was undertaken within 590 primary care practices in England, United Kingdom. 8,777 patients diagnosed with pancreatic cancer (cases) between 1st January 2007 and 31st August 2020 were matched to 34,979 controls by age, gender and diabetes. Longitudinal trends in BMI and HbA1c were visualised. Odds ratios adjusted for demographic and lifestyle factors (aOR) and 95% confidence intervals (CI) were calculated with conditional logistic regression. Subgroup analyses were undertaken according to the diabetes status.



    Changes in BMI and HbA1c observed for cases on longitudinal plots started one and two years (respectively) before diagnosis. In the year before diagnosis, a 1 kg/m2 decrease in BMI between cases and controls was associated with aOR for pancreatic cancer of 1.05 (95% CI 1.05 to 1.06), and a 1 mmol/mol increase in HbA1c was associated with aOR of 1.06 (1.06 to 1.07). ORs remained statistically significant (p < 0.001) for 2 years before pancreatic cancer diagnosis for BMI and 3 years for HbA1c. Subgroup analysis revealed that the decrease in BMI was associated with a higher pancreatic cancer risk for people with diabetes than for people without (aORs 1.08, 1.06 to 1.09 versus 1.04, 1.03 to 1.05), but the increase in HbA1c was associated with a higher risk for people without diabetes than for people with diabetes (aORs 1.09, 1.07 to 1.11 versus 1.04, 1.03 to 1.04).



    The statistically significant changes in weight and glycaemic control started three years before pancreatic cancer diagnosis but varied according to the diabetes status. The information from this study could be used to detect pancreatic cancer earlier than is currently achieved. However, regular BMI and HbA1c measurements are required to facilitate future research and implementation in clinical practice.

    William Hinton, Abdus Samad Ansari, Martin B. Whyte, Andrew P. McGovern, Michael D. Feher, Neil Munro, Simon de Lusignan (2022) Sodium–glucose co‐transporter‐2 (SGLT2) inhibitors and heart failure in type 2 diabetes: Are clinical trial benefits reflected in real-world clinical practice? A systematic review and meta-analysis of observational studies
    Diabetes, Obesity and Metabolism 2023 Feb;25(2):501-515. doi: 10.1111/dom.14893. Epub 2022 Nov 2.

    Aim: To determine the absolute risk reduction (ARR) of heart failure events in people treated with sodium-glucose co-transporter-2 (SGLT2) inhibitors.

    Materials and methods: We searched PubMed, EMBASE, CINAHL and ISI Web of Science for observational studies published to 9 May 2022 that explored the association between SGLT2 inhibitors and any indication for heart failure (including new diagnosis or hospitalization for heart failure) in type 2 diabetes. Identified studies were independently screened by two reviewers and assessed for bias using the Newcastle-Ottawa scale. Eligible studies with comparable outcome data were pooled for meta-analysis using random-effects models, reporting hazard ratios (HRs) with 95% confidence intervals (CIs). The ARR per 100 person-years was determined overall, and in subgroups with and without baseline cardiovascular disease (CVD).

    Results: From 43 eligible studies, with a total of 4 818 242 participants from 17 countries, 21 were included for meta-analysis. SGLT2 inhibitors were associated with a reduced risk of hospitalization for heart failure (HR 0.65, 95% CI 0.59-0.72) overall and both in those with CVD (HR 0.78, 95% CI 0.68-0.89) and without CVD (HR 0.53, 95% CI 0.39-0.71). Risk reduction for hospitalization for heart failure in people with a history of CVD (ARR 1.17, 95% CI 0.78-1.55) was significantly greater than for those without CVD (ARR 0.39, 95% CI 0.32-0.47). The number-needed-to-treat to prevent one event of hospitalization for heart failure was 86 (95% CI 65-128) person-years of treatment for the CVD group and 256 (95% CI 215-316) person-years for those without CVD.

    Conclusions: Real-world SGLT2 inhibitor use supports randomized trial data for the size effect of reduced hospitalization for heart failure in type 2 diabetes, although with a much lower ARR in people without CVD.

    Charlwood C, Chudasama J, Darling A, Logan Ellis H, Whyte MB (2023) Effect of Sodium Glucose Co-Transporter 2 Inhibitors on plasma potassium: a meta-analysis.
    Diabetes Research & Clinical Practice 2023 Jan 5;196:110239. doi: 10.1016/j.diabres.2023.110239.


    There has been uncertainty whether SGLT2 inhibition predisposes to hyperkalaemia or is protective from it. We therefore performed a meta-analysis to assess effects of SGLT2 inhibition on serum-potassium and hyperkalaemia-events in T2DM.


    MEDLINE and PubMed databases were searched for ‘hyperkalaemia’ or ‘potassium’, with SGLT2 inhibitors in T2DM, to 31st December 2020. Randomised controlled trials, with potassium or hyperkalaemia as primary or secondary outcomes, were included. Cochran’s Q test and I2 statistic assessed statistical heterogeneity. Meta-analyses were performed using Cochrane-RevMan with two outcomes: i) Odds ratio (OR) of hyperkalaemia-events between SGLT2 inhibitor and placebo (fixed-effects), ii) Mean difference (MD) in change from baseline potassium between SGLT2 inhibitor and placebo (random-effects).


    Of 1724 identified publications, nine were included in the meta-analysis (n=3 hyperkalaemia event; n=5 serum-potassium; n=1 reported both outcomes). Pooled OR for hyperkalaemia-events for SGLT2 inhibitor vs placebo was 0.72 [95% confidence interval (CI) 0.61 to 0.85, P<0.001], I2 of 9%. The pooled MD in serum-potassium concentration with SGLT2 inhibitor vs placebo was -0.04 mmol/L [95% CI -0.08 to 0.00 mmol/L; P=0.04], I2 of 89%.


    Use of SGLT2 inhibitors in T2DM reduced odds of inducing hyperkalaemia but had a minimal effect of lowering serum potassium.

    William Maclean, Sally C Benton, Martin B Whyte, Timothy Rockall, Iain Jourdan (2023) Efficacy and accuracy of faecal sampling by a digital rectal examination for FIT
    Ann Clin Biochem. 2023 Jan 19;45632231155021. doi: 10.1177/00045632231155021. Online ahead of print.

    Aim: A digital rectal examination (DRE) during routine assessment for patients with abdominal symptoms provides an opportunity to obtain faeces from the glove for faecal immunochemical testing (FIT). Here, we compared sampling via DRE to the standard faecal sampling by patients.

    Method: Patients were recruited to a prospective observational cohort study between July 2019 and March 2020. Patients provided a sample for the FOB Gold Wide® which was compared to a further sample taken at clinic via DRE. Clinicians reported whether they obtained a "good" sample filling all the grooves, a "poor" sample filling some of the grooves or no faecal sample. Cohen's kappa was used to compare percentage agreement around a negative threshold of <10 μg haemoglobin/g of faeces. Sensitivity for serious bowel disease (SBD) was calculated.

    Results: Of 596 patients who underwent attempted DRE sampling, there were 258 (43.3%) "good" samples, 117 (19.6%) "poor" samples and 221 (37.1%) with no sample to wipe in the grooves. Cohen's kappa dropped from 0.70 to 0.30 for the "good" and "poor" samples respectively. Of those with DRE samples and definitive diagnostic outcomes, the sensitivity for SBD dropped significantly from 76.0% to 41.7% between "good" and "poor" samples respectively (p=0.041).

    Conclusions: A "good" sample obtained by DRE provides comparable results to samples obtained by patients. This creates potential benefit in speed and ease of testing for patients. However, not all DRE sampling attempts are successful, and the clinician must be satisfied that enough faeces is obtained to wipe adequately into all grooves.

    Nicholas G Farkas, James O’Brien, Martin Whyte, Iain Jourdan, Tim Rockall, Sally C Benton (2023) An observational cohort study of replicate FIT in symptomatic two-week wait patients
    Annals of Clinical Biochemistry 2023 Mar 14;45632231163425. doi: 10.1177/00045632231163425.

    Introduction: Triage of patients with suspected colorectal cancer (CRC) utilises a single faecal immunochemical test (FIT) at a defined threshold. Limited evidence exists regarding whether replicate FIT improves the positive and negative predictive value in symptomatic patients. This study examines urgently referred symptomatic patients undergoing replicate FIT. Primary aim is to assess two FITs and CRC/serious bowel disease. Secondary aims are to determine correlation and utility of replicate FIT.

    Methodology: Patients carried out one additional FIT during COVID-19 pandemic. FIT 1 and FIT 2 (the replicate sample) were analysed in relation to symptoms, diagnoses, investigations, future colonoscopy and missed CRC. Study period was 01/03/2020-31/07/2020. Three subgroups were compared; double positive (≥10 μg Hb/g faeces), double negative, and discordant FIT (one positive).

    Results: 111 patients had replicate FIT (50 male, 61 female). 43 (38.7%) patients had double negative, 32 (28.8%) double positive and 36 (32.4%) had discordant FITs. Median time between FITs was 14 days (IQR = 11-19). 83% of double positive patients underwent colonoscopy/virtual colonoscopy (61% in double negative patients). Six CRC and one high-risk polyp were in double positive patients (none in other groups). One discordant patient was not investigated and a CRC missed.

    Conclusions: Replicate FIT as a triage strategy appears most effective where both FITs are negative. CRC risk is low when FIT results are discordant. Double negative FITs are reassuring given benign associated diagnoses, or for patients where endoscopic investigation is high-risk. Larger studies are required to evaluate discordant FITs, enabling refinement of urgent investigation pathways.

    Anna Maria Geretti, Harrison Austin, Giovanni Villa, Colette Smith, Caroline Sabin, Filipa Ferreira, Rachel Byford, Bernardo Meza-Torres, Martin Whyte, Simon de Lusignan (2023) Hepatitis B virus (HBV) infection in general practice across England: Data from the Royal College of General Practitioners Research and Surveillance Network Centre


    We analysed hepatitis B surface antigen (HBsAg) screening and seropositivity within a network of 419 general practices representative of all regions of England.


    Information was extracted using pseudonymised registration data. Predictors of HBsAg seropositivity were explored in models that considered age, gender, ethnicity, time at the current practice, practice location and associated deprivation index, and presence of nationally endorsed screen indicators including pregnancy, men who have sex with men (MSM), history of injecting drug use (IDU), close HBV contact or imprisonment, and diagnosis of blood-borne or sexually transmitted infections.


    Among 6,975,119 individuals, 192,639 (2.8%) had a screening record, including 3.6- 38.6% of those with a screen indicator, and 8065 (0.12%) had a seropositive record. The odds of seropositivity were highest in London, in the most deprived neighbourhoods, among minority ethnic groups, and in people with screen indicators. Seroprevalence exceeded 1% in people from high prevalence countries, MSM, close HBV contacts, and people with a history of IDU or HIV, HCV, or syphilis diagnosis. Overall, 1989/8065 (24.7%) had a recorded referral to specialist hepatitis care.


    In England, HBV infection is associated with poverty. There are unrealised opportunities to promote access to diagnosis and care for those affected.

    Beatriz Burger, Daniel White, Roberta Sagiorato, Jéssica Silva, Thamiris Candreva, Mariana Pacheco, Bianca Castelucci, Laís Pral, Helena Fisk, Izadora Alves, Jefferson Elias-Oliveira, Wislei Osório, Sílvio Consonni, Marco Aurélio Vinolo, Philip Calder, Cl (2023) Eicosapentaenoic acid-rich oil supplementation activates PPAR-γ and delays skin wound healing in type 1 diabetic mice.
    Frontiers of Immunology 2023; 14: 1141731

    Delayed wound healing is a devastating complication of diabetes and supplementation with fish oil, a source of anti-inflammatory omega-3 (ω-3) fatty acids including eicosapentaenoic acid (EPA), seems an appealing treatment strategy. However, some studies have shown that ω-3 fatty acids may have a deleterious effect on skin repair and the effects of oral administration of EPA on wound healing in diabetes are unclear. We used streptozotocin-induced diabetes as a mouse model to investigate the effects of oral administration of an EPA-rich oil on wound closure and quality of new tissue formed. Gas chromatography analysis of serum and skin showed that EPA-rich oil increased the incorporation of ω-3 and decreased ω-6 fatty acids, resulting in reduction of the ω-6/ω-3 ratio. On the tenth day after wounding, EPA increased production of IL-10 by neutrophils in the wound, reduced collagen deposition, and ultimately delayed wound closure and impaired quality of the healed tissue. This effect was PPAR-γ-dependent. EPA and IL-10 reduced collagen production by fibroblasts in vitroIn vivo, topical PPAR-γ-blockade reversed the deleterious effects of EPA on wound closure and on collagen organization in diabetic mice. We also observed a reduction in IL-10 production by neutrophils in diabetic mice treated topically with the PPAR-γ blocker. These results show that oral supplementation with EPA-rich oil impairs skin wound healing in diabetes, acting on inflammatory and non-inflammatory cells.

    George JM, White DS, Fielding BA, Scott MJ, Rockall TA, Whyte MB (2023) Systematic Review of Preoperative Omega-3 Fatty Acids in Major Gastrointestinal Surgery
    BMJ Surgery, Interventions, & Health Technologies. 2023; 5(1): e000172

    Objectives Perioperative nutrition aims to replenish nutritional stores before surgery and reduce postoperative complications. ‘Immunonutrition’ (including omega-3 fatty acids) may modulate the immune system and attenuate the postoperative inflammatory response. Hitherto, immunonutrition has overwhelmingly been administered in the postoperative period—however, this may be too late to provide benefit.

    Design A systematic literature search using MEDLINE and EMBASE for randomized controlled trials (RCTs).

    Setting Perioperative major gastrointestinal surgery.

    Participants Patients undergoing major gastrointestinal surgery.

    Interventions Omega-3 fatty acid supplementation commenced in the preoperative period, with or without continuation into postoperative period.

    Main outcome measures The effect of preoperative omega-3 fatty acids on inflammatory response and clinical outcomes.

    Results 833 studies were identified. After applying inclusion and exclusion criteria, 12 RCTs, involving 1456 randomized patients, were included. Ten articles exclusively enrolled patients with cancer. Seven studies used a combination of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) as the intervention and five studies used EPA alone. Eight out of 12 studies continued preoperative nutritional support into the postoperative period.

    Of the nine studies reporting mortality, no difference was seen. Duration of hospitalisation ranged from 4.5 to 18 days with intervention and 3.5 to 23.5 days with control. Omega-3 fatty acids had no effect on postoperative C-reactive protein and the effect on cytokines (including tumor necrosis factor-α, interleukin (IL)-6 and IL-10) was inconsistent. Ten of the 12 studies had low risk of bias, with one study having moderate bias from allocation and blinding.

    Conclusions There is insufficient evidence to support routine preoperative omega-3 fatty acid supplementation for major gastrointestinal surgery, even when this is continued after surgery.

    Lacey, H; Attersley-Smith, S; Stone, S; Whyte, M.B; Shawe, J; Hart, K (2023) Quality of life improvements after bariatric surgery in reproductive age women with and without PCOS: a cohort study
    Minerva Obstetrics and Gynaecology 2023; 75(3): 251-259

    BACKGROUND: Obesity can negatively influence quality of life (QoL). Polycystic ovarian syndrome (PCOS), associated with obesity, presents with sub-fertility, hyperandrogenism, and/or insulin resistance. These features can also negatively influence QoL. This study aimed to determine whether bariatric surgery improves QoL in women of reproductive age, with and without PCOS. We hypothesized greater QoL improvements would be seen post-operatively in women with PCOS.
    METHODS: Women undergoing bariatric surgery (N.=77) completed questionnaires exploring health-related quality of life (HR-QoL) prior to and at 3, 6 and 12 months post-surgery. Weight loss, symptoms, and association with change in QoL were assessed.
    RESULTS: Bariatric surgery resulted in significant QoL improvements, independent of PCOS status. Oligo/amenorrhea was reported in 68% of women at baseline, decreasing to 35% by 12 months. Sixty-five percent of women whose menstrual irregularity resolved over follow-up had PCOS. Hirsutism was reported in 64% of women at baseline (all of whom had PCOS), decreasing to 19% by 12 months. Weight loss at 12-months was 45.8±20.7 kg for women without PCOS compared to 44.3±16.8 kg in women with PCOS (P=0.07). Weight loss was moderately associated with 12-month QoL improvements for both groups.
    CONCLUSIONS: Bariatric surgery provides significant physical and psychological health benefits for women with obesity both with and without PCOS. Surgery can also ameliorate the clinical syndrome of PCOS, including oligomenorrhoea, hirsutism, and subfertility, with subsequent QoL benefits. Psychological support perioperatively may aid QoL outcomes by acknowledging factors influencing QoL beside absolute weight loss.

    H Logan-Ellis, D.Llewellyn, J.Mendis, M.Whyte (2023) Admission plasma potassium and length of hospital stay: a meta-analysis
    BMJ Open. 2023 Aug 24;13(8):e068387. doi: 10.1136/bmjopen-2022-068387.

    Objective: Hypokalaemia and hyperkalaemia ('dyskalaemia') are commonly seen in patients requiring emergency hospital admission. The adverse effect of dyskalaemia on mortality is well described but there are few data for the effect on hospital length of stay. We sought to determine the association of serum potassium concentration with in-hospital length of stay.

    Design: Systematic review and meta-analysis.

    Data sources: A structured search of MEDLINE, PubMed and SCOPUS databases to 19 March 2021.

    Eligibility criteria: Observational cohort studies defining exposure of interest as serum potassium levels (at admission or within the first 72 hours) and with outcome of interest as length of hospital stay. Studies had to provide estimates of length of stay as a comparison between normokalaemia and defined ranges of hyperkalaemia or hypokalaemia.

    Data extraction and synthesis: We identified 39 articles published to March 2021 that met the inclusion and exclusion criteria. Study selection, data extraction and quality assessment were carried out by two reviewers working independently and in duplicate, to assessed eligibility and risk of bias, and extract data from eligible studies. Random effects models were used to pool estimates across the included studies. Meta-analyses were performed using Cochrane-RevMan.

    Results: Five studies were included in the meta-analysis. Compared with the reference group (3.5-5.0 mmol/L), the pooled raw differences of medians were 4.45 (95% CI 2.71 to 6.91), 1.99 (95% CI 0.03 to 3.94), 0.98 (95% CI 0.91 to 1.05), 1.51 (95% CI 1.03 to 2.0), 1 (95% CI 0.75 to 1.25) and 2.76 (95% CI 1.24 to 4.29) for patients with potassium levels of <2.5, 2.5 to <3.0, 3.0 to <3.5, <5 to 5.5, <5.5 to 6 and >6.0 mmol/L, respectively.

    Conclusion: Hospital length of stay follows a U-shaped distribution, with duration of admission being twofold greater at the extremes of the potassium range.

    Mike Stedman, Martin Whyte, Ian Laing, Anthony Fryer, Bernardo Meza Torres, Gerry Rayman, Adam Robinson, Martin Gibson, Adrian Heald (2023) Failure to control conventional cardiovascular risk factors in women with type 2 diabetes might explain worse mortality
    Diabetes Metabolism Research & Reviews 2023 Aug 17;e3695. doi: 10.1002/dmrr.3695. Online ahead of print.


    The standardised mortality rate (SMR) for people with diabetes in England is 1.5–1.7, with differences in outcomes between sexes. There has been little work examining the factors that could have an impact on this or on what may determine sex differences in outcome.


    Data were extracted for patients with type 2 diabetes (T2D) in Salford (England) in 2010 for the years up to 2020, including any deaths recorded. Expected deaths were calculated from annual Office of National Statistics mortality rate and life expectancy by age and gender, adjusted for the local Index of Multiple Deprivation (IMD). This provided the SMR deprivation (SMRd), and life expectancy years lost per death (LEYLD). The effects of treatment type, and clinical features on SMRd relative to sex were examined by univariable and multivariable analysis.


    Data from n = 11,806 (F = 5184; M = 6622) patients were included. Of these, n = 5540 were newly diagnosed and n = 3921 died (F = 1841; M = 2080). In total, n = 78,930 patient years. The expected deaths numbered n = 2596 (adjusted for age, sex, and IMD). Excess deaths were n = 1325 (F = 689; M = 636). Life expectancy years lost (LEYL) 18,989 (F = 9714; M = 9275). SMRd 1.51 (F = 1.60; M = 1.44) and LEYLD 4.84 years (F = 5.28; M = 4.46). The impact of risk factors was not different by sex. However, women had higher prevalence of % diagnosed >65 years of age; % last eGFR <60 mLs/min/1.73 m2, and lower prevalence of % prescribed ACE-inhibitor/ARB, DPP4-inhibitor and SGLT2-inhibitor. Applying the male prevalence rate to the female population and expected mortality suggested n = 437 (55%) of excess T2D female deaths were attributed to sex difference in the prevalence of these risk and protective factors.


    Outcomes in women with T2DM are worse than in men, contributed to by greater prevalence of adverse factors and less prescribing of cardioprotective medication.

    Alexander D. Rodway, Jenny Harris, Ciara Giltinan, Ali Dehghan-Nayeri, Andre Santos ,Lydia Hanna, Felipe Pazos Casal, Charlotte Allan, Martin B. Whyte, Nikolaos Ntagiantas, Ivan Walton, Richard Brown, Simon S. Skene, Ajay Pankhania, Benjamin C. T. Field, (2023) Understanding the Impact of COVID-19 on Angioplasty Service and Outcome of Patients Treated for Chronic Limb-Threatening Ischaemia: A Single-Centre Retrospective Cohort Study
    Biomedicines 2023, 11(7), 2034

    We evaluated the impact of COVID-19 restriction on the angioplasty service and outcome of chronic limb-threatening ischaemia (CLTI) patients undergoing lower-limb angioplasty in a UK secondary care setting. Consecutive patients were analysed retrospectively. Pre-COVID-19 (08/2018–02/2020), 106 CLTI patients (91% Fontaine 4; 60% diabetes mellitus) and during COVID-19 (03/2020–07/2021) 94 patients were treated (86% Fontaine 4; 66% diabetes mellitus). While the average monthly number of patients treated did not change, the proportion of day cases significantly increased (53% to 80%), and hospitalised patients decreased. Patients treated in £14/5 days after referral significantly increased to 64/63%. Kaplan–Meier survival analysis (30-day/1-year) showed that neither wound healing nor mortality were significantly changed during COVID-19. In day cases, 1-year but not 30-day major amputations significantly increased, and clinically driven target-lesion revascularisation decreased during COVID-19. One-year mortality was significantly worse in hospitalised compared to day cases (14% vs. 43%) at similar wound healing rates (83% vs. 84%). The most frequent known cause of death was infectious disease (64%), while cardiovascular (21%) was less frequent. Despite COVID-19 restrictions, a safe and effective angioplasty service was maintained while shortening waiting times. Very high mortality rates in hospitalised patients may indicate that CLTI patients need to be referred and treated more aggressively earlier.

    Hannah Baggott, Martin Whyte, Luke Hodgson, Lui Forni (2023) A multi-national survey to identify health professionals’ opinions for the appropriate frequency of urine output monitoring in post-operative patients.
    Journal of the Intensive Care Society Sept 2023 https://doi.org/10.1177/17511437231199900

    Urine output is an important clinical measurement and oliguria may highlight the development of acute kidney injury (AKI) earlier than serum creatinine (sCr). Despite the importance of urine output monitoring, there are no definitive guidelines or recommendations for best practice. A survey was sent to healthcare professionals with a specialist interest in AKI to gather opinions of what constitutes a good standard of urine output monitoring and by corollary missed care, post- major surgery. Data was gathered from 221 respondents. Results will inform audit and improvement projects in post-operative nursing care.

    Mike Stedman, Adam Robinson, George Dunn, Bernado Meza-Torres, J Martin Gibson, Neil D. Reeves, Michael Feher, Gerry Rayman, Martin Whyte, Michael Edmonds, Adrian Heald (2023) Diabetes Foot Complications and Standardized Mortality Rate in Type 2 Diabetes
    Diabetes, Obesity and Metabolism 2023 Sep 18. doi: 10.1111/dom.15260. Online ahead of print.


    To quantify the impact of foot complications on mortality outcomes in people with type 2 diabetes (T2D), and how routinely measured factors might modulate that risk.

    Materials and Methods

    Data for individuals with T2D for 2010-2020, from the Salford Integrated Care Record (Salford, UK), were extracted for laboratory and clinical data, and deaths. Annual expected deaths were taken from Office of National Statistics mortality data. An index of multiple deprivation (IMD) adjusted the standardized mortality ratio (SMR_IMD). Life years lost per death (LYLD) was estimated from the difference between expected and actual deaths.


    A total of 11 806 T2D patients were included, with 5583 new diagnoses and 3921 deaths during 2010-2020. The number of expected deaths was 2135; after IMD adjustment, there were 2595 expected deaths. Therefore, excess deaths numbered 1326 (SMR_IMD 1.51). No foot complications were evident in n = 9857. This group had an SMR_IMD of 1.13 and 2.74 LYLD. In total, 2979 patients had any foot complication recorded. In this group, the SMD_IMR was 2.29; of these, 2555 (75%) had only one foot complication. Patients with a foot complication showed little difference in percentage HbA1c more than 58 mmol/mol. In multivariate analysis, for those with a foot complication and an albumin-to-creatinine ratio of more than 3 mg/mmol, the odds ratio (OR) for death was 1.93, and for an estimated glomerular filtration rate of less than 60 mL/min/1.73m2, the OR for death was 1.92.


    Patients with T2D but without a foot complication have an SMR_IMD that is only slightly higher than that of the general population. Those diagnosed with a foot complication have a mortality risk that is double that of those without T2D.

    Bernardo Meza-Torres, Gayathri Delanerolle, Anna Forbes, William Elson, Debasish Kar, Gavin Jamie, William Hinton, Carole Aspen, Xuejuan Fan, Rachel Byford, Michael Feher, Martin Whyte, Mark Joy, F.D. Richard Hobbs, Simon de Lusignan (2023) Hepatitis A vaccination coverage amongst people with Chronic Liver Disease in England (HEALD): protocol for a retrospective cohort study.
    JMIR Research Protocols 12(1), e51861, 2023

    Hepatitis A outbreaks in the United Kingdom are uncommon. Most people develop mild-to-moderate symptoms that resolve, without sequelae, within months. However, in high-risk groups, including those with underlying chronic liver disease, hepatitis A infection can be severe, with higher risk of mortality and morbidity. The UK’s public health body, the Health Security Agency and the English guidelines organisation, the National Institute of Health and Care Excellence, recommend pre-exposure hepatitis A vaccination given as two doses to people with chronic liver disease, regardless of its cause. There are currently no published reports of vaccination coverage in people with chronic liver disease in England, or internationally.


    To describe hepatitis A vaccination coverage in adults with chronic liver disease in a UK primary care setting. To compare liver disease aetiology, sociodemographic characteristics and comorbidities in people who are and are not exposed to hepatitis A vaccine.


    This is a retrospective cohort study with data from the Primary Care Sentinel Cohort of the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub (ORCHID) database; nationally representative of the English population. We will include people 18 years of age and older who have been registered in general practices in the RSC network and have a record of chronic liver disease between 01-01-2012 and 31-12-2022, including those with alcohol related liver disease, chronic hepatitis B, chronic hepatitis C, non-alcohol fatty liver disease, Wilson’s disease, haemochromatosis, and autoimmune hepatitis. We will carefully curate variables using the Systematized Nomenclature of Medicine Clinical Terms. We will report the sociodemographic characteristics of those who are vaccinated. These include: age, gender, ethnicity, population density, region, socioeconomic status (measured using the index of multiple deprivation), obesity, alcohol consumption and smoking. Hepatitis A vaccination coverage for one and two doses will be calculated using an estimate of the chronic liver disease population as the denominator. We will analyse the baseline characteristics using descriptive statistics including measures of dispersion. Pairwise comparisons of case-mix characteristics, comorbidities and complications will be reported according to vaccination status. A multistate survival model will be fitted to estimate the transition probabilities between four states: 1) Diagnosed with CLD, 2) First dose of hepatitis A vaccination, 3) Second dose of hepatitis A vaccination, 4) Death. This will identify any potential disparities in which people with chronic liver disease get vaccinated.


    The RSC population comprises over 8 million people. The reported incidence of chronic liver disease is 20.7 cases per 100,000. International estimates of Hepatitis A vaccine coverage vary between 10 to 50% in this group.


    This study will describe the uptake of hepatitis A vaccine in people with CLD and report any disparities or differences in characteristics of the vaccinated population

    Reuben Reed, Martin B Whyte, Louise Goff () Cardiometabolic disease in black African and Caribbean populations: an ethnic divergence in pathophysiology?
    Proceedings of the Nutrition Society. Accepted for publication November 2023
    Banne Nemeth, Mark Smeets, Alma Becic Pedersen, Eskild Bendix Kristiansen, Rob Nelissen, Martin Whyte, Lara Roberts, Simon de Lusignan, Saskia le Cessie, Suzanne Cannegieter, Roopen Arya (2023) Development and validation of a clinical prediction model for 90-day venous thromboembolism risk following total hip and total knee arthroplasty: a multinational study.
    Journal of Thrombosis and Haemostasis Nov 2023 https://doi.org/10.1016/j.jtha.2023.09.033


    The risk of venous thromboembolism (VTE) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) is 1.0% to 1.5%, despite uniform thromboprophylaxis.


    To develop and validate a prediction model for 90-day VTE risk.


    A multinational cohort study was performed. For model development, records were used from the Oxford Royal College of General Practitioners Research and Surveillance Centre linked to Hospital Episode Statistics and Office of National Statistics UK routine data. For external validation, data were used from the Danish Hip and Knee Arthroplasty Registry, the National Patient Registry, and the National Prescription Registry. Binary multivariable logistic regression techniques were used for development.


    In the UK data set, 64 032 THA/TKA procedures were performed and 1.4% developed VTE. The prediction model consisted of age, body mass index, sex, cystitis within 1 year before surgery, history of phlebitis, history of VTE, presence of varicose veins, presence of asthma, history of transient ischemic attack, history of myocardial infarction, presence of hypertension and THA or TKA. The area under the curve of the model was 0.65 (95% CI, 0.63-0.67). Furthermore, 36 169 procedures were performed in the Danish cohort, of whom 1.0% developed VTE. Here, the area under the curve was 0.64 (95% CI, 0.61-0.67). The calibration slope was 0.92 in the validation study and 1.00 in the development study.


    This clinical prediction model for 90-day VTE risk following THA and TKA performed well in both development and validation data. This model can be used to estimate an individual’s risk for VTE following THA/TKA.