Clinical practice guidelines for management of hyperglycaemia in adults with diabetic kidney disease.

A significant percentage of people with diabetes develop chronic kidney disease and diabetes is also a leading cause of end-stage kidney disease (ESKD). The term diabetic kidney disease (DKD) includes both diabetic nephropathy (DN) and diabetes mellitus and chronic kidney disease (DM CKD). DKD is associated with high morbidity and mortality, which are predominantly related to cardiovascular disease. Hyperglycaemia is a modifiable risk factor for cardiovascular complications and progression of DKD. Recent clinical trials of people with DKD have demonstrated improvement in clinical outcomes with sodium glucose co-transporter-2 (SGLT-2) inhibitors. SGLT-2 inhibitors have significantly reduced progression of DKD and onset of ESKD and these reno-protective effects are independent of glucose lowering. At the time of this update Canagliflozin and Dapagliflozin have been approved for delaying the progression of DKD. The Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) Diabetic Kidney Disease Clinical Speciality Group have undertaken a literature review and critical appraisal of the available evidence to inform clinical practice guidelines for management of hyperglycaemia in adults with DKD. This 2021 guidance is for the variety of clinicians who treat people with DKD, including GPs and specialists in diabetes, cardiology and nephrology.

Association of British Clinical Diabetologists (ABCD) and Diabetes UK joint position statement and recommendations on the use of sodium-glucose cotransporter inhibitors with insulin for treatment of type 1 diabetes (Updated October 2020).

Dapagliflozin (SGLT-2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) are two of the drugs of SGLT inhibitor class which have been recommended by the National Institute for Health and Care Excellence (NICE) in people with type 1 diabetes with BMI ≥27 kg/m2 . Dapagliflozin is licensed in the UK for use in the NHS while sotagliflozin may be available in future. These and possibly other SGLT inhibitors may be increasingly used in people with type 1 diabetes as new licences are obtained. These drugs have the potential to improve glycaemic control in people with type 1 diabetes with the added benefit of weight loss, better control of blood pressure and more time in optimal glucose range. However, SGLT inhibitors are associated with a higher incidence of diabetic ketoacidosis without significant hyperglycaemia. The present ABCD/Diabetes UK joint updated position statement is to guide people with type 1 diabetes and clinicians using these drugs help mitigate this risk and other potential complications. Particularly, caution needs to be exercised in people who are at risk of diabetic ketoacidosis due to low calorie diets, illnesses, injuries, starvation, excessive exercise, excessive alcohol consumption and reduced insulin administration among other precipitating factors for diabetic ketoacidosis.

Association of British Clinical Diabetologists and Renal Association guidelines on the detection and management of diabetes post solid organ transplantation.

Post-transplant diabetes mellitus (PTDM) is common after solid organ transplantation (SOT) and associated with increased morbidity and mortality for allograft recipients. Despite the significant burden of disease, there is a paucity of literature with regards to detection, prevention and management. Evidence from the general population with diabetes may not be translatable to the unique context of SOT. In light of emerging clinical evidence and novel anti-diabetic agents, there is an urgent need for updated guidance and recommendations in this high-risk cohort. The Association of British Clinical Diabetologists (ABCD) and Renal Association (RA) Diabetic Kidney Disease Clinical Speciality Group has undertaken a systematic review and critical appraisal of the available evidence. Areas of focus are; (1) epidemiology, (2) pathogenesis, (3) detection, (4) management, (5) modification of immunosuppression, (6) prevention, and (7) PTDM in the non-renal setting. Evidence-graded recommendations are provided for the detection, management and prevention of PTDM, with suggested areas for future research and potential audit standards. The guidelines are endorsed by Diabetes UK, the British Transplantation Society and the Royal College of Physicians of London. The full guidelines are available freely online for the diabetes, renal and transplantation community using the link below. The aim of this review article is to introduce an abridged version of this new clinical guideline ( https://abcd.care/sites/abcd.care/files/site_uploads/Resources/Position-Papers/ABCD-RA%20PTDM%20v14.pdf).

Community-based pre-pregnancy care programme improves pregnancy preparation in women with pregestational diabetes.

AIMS/HYPOTHESIS: Women with diabetes remain at increased risk of adverse pregnancy outcomes associated with poor pregnancy preparation. However, women with type 2 diabetes are less aware of and less likely to access pre-pregnancy care (PPC) compared with women with type 1 diabetes. We developed and evaluated a community-based PPC programme with the aim of improving pregnancy preparation in all women with pregestational diabetes. METHODS: This was a prospective cohort study comparing pregnancy preparation measures before and during/after the PPC intervention in women with pre-existing diabetes from 1 June 2013 to 28 February 2017. The setting was 422 primary care practices and ten National Health Service specialist antenatal diabetes clinics. A multifaceted approach was taken to engage women with diabetes and community healthcare teams. This included identifying and sending PPC information leaflets to all eligible women, electronic preconception care templates, online education modules and resources, and regional meetings and educational events. Key outcomes were preconception folic acid supplementation, maternal HbA1c level, use of potentially harmful medications at conception and gestational age at first presentation, before and during/after the PPC programme. RESULTS: A total of 306 (73%) primary care practices actively participated in the PPC programme. Primary care databases were used to identify 5075 women with diabetes aged 18-45 years. PPC leaflets were provided to 4558 (89.8%) eligible women. There were 842 consecutive pregnancies in women with diabetes: 502 before and 340 during/after the PPC intervention. During/after the PPC intervention, pregnant women with type 2 diabetes were more likely to achieve target HbA1c levels ≤48 mmol/mol (6.5%) (44.4% of women before vs 58.5% of women during/after PPC intervention; p = 0.016) and to take 5 mg folic acid daily (23.5% and 41.8%; p = 0.001). There was an almost threefold improvement in 'optimal' pregnancy preparation in women with type 2 diabetes (5.8% and 15.1%; p = 0.021). Women with type 1 diabetes presented for earlier antenatal care during/after PPC (54.0% vs 67.3% before 8 weeks' gestation; p = 0.003) with no other changes. CONCLUSIONS/INTERPRETATION: A pragmatic community-based PPC programme was associated with clinically relevant improvements in pregnancy preparation in women with type 2 diabetes. To our knowledge, this is the first community-based PPC intervention to improve pregnancy preparation for women with type 2 diabetes. DATA AVAILABILITY: Further details of the data collection methodology, individual clinic data and the full audit reports for healthcare professionals and service users are available from https://digital.nhs.uk/data-and-information/clinical-audits-and-registries/our-clinical-audits-and-registries/national-pregnancy-in-diabetes-audit .

Managing diabetic kidney disease.

Introduction: Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). This review covers the pillars of care essential for the management of diabetic kidney disease (DKD) including (1) early diagnosis, (2) improved glycaemic control, (3) treatment of hypertension, (4) identification and treatment of associated metabolic bone disease and (5) identification and effective management of dyslipidaemia and additional cardiovascular risk factors. Sources of data: We searched PubMed for articles using search terms: diabetic nephropathy, diabetic kidney disease, diabetes and chronic kidney disease. We used clinical guidelines from NICE, the Association of British Clinical Diabetologists (ABCD), the Joint British Societies (JBS) and the Kidney Disease: Improving Global Outcomes (KDIGO) working group. Areas of agreement: Multiple risk factor reduction targeting glycaemic control, blood pressure control, dyslipidaemia, smoking and management of obesity is important in preventing and in managing DKD. Areas of controversy: Guidelines disagree on the individualized glycaemic targets for patients with diabetic kidney disease. Growing points: The growing number of patients with DKD is causing increased pressure on limited primary care and specialized services. New ways of managing patients using novel technology solutions are required. Areas timely for development: The use of novel anti-hyperglycaemic agents, particularly sodium glucose co-transporter 2 inhibitors and GLP-1 receptor agonists, has been associated with a reduction in cardiovascular disease and DKD.

Diabetes confers in vitro calcific potential on serum which associates with in vivo vascular calcification.

Although vascular calcification (VC) is prevalent in Type 2 diabetes mellitus (T2DM), underlying mechanisms remain unclear. Neither is it known whether T2DM confers calcific potential (CP) on serum, enabling it to induce VC outside the disease milieu. We, therefore, investigated the CP of serum from controls and subjects with T2DM with and without in vivo VC. Samples from 20 healthy controls and 44 age- and sex-matched patients with T2DM with modification of diet in renal disease estimated glomerular filtration rate (MDRD-4 eGFR) > 60 ml·min-1 were analysed for CP using rat aortic smooth muscle cells in vitro CT scans of femoral arteries identified individuals with in vivo calcification. Serum from subjects with T2DM revealed significantly greater CP than controls. This was further enhanced in the presence of in vivo VC. Addition of ß-glycerophosphate (ß-GP) plus CaCl2 increased the CP of T2DM serum but not of controls. Along with age, CP was an independent predictor of the presence of VC. In receiver operator curve (ROC) analysis, CP was a significant predictor of femoral arterial VC (C-statistic 0.70: P=0.009). The distribution of CP was bimodal around a cutoff of 100 nmoles of Ca2+ protein mg-1, with a higher proportion of Type 2 diabetes subjects with in vivo calcification (T2DM+) sera above the cutoff value. This group also showed elevated levels of osteoprotegerin (OPG) and matrix Gla protein (MGP). Diabetes confers CP on the serum which is enhanced by the presence of in vivo VC. The CP acquired may be dependent on levels of OPG and MGP. These findings may be clinically relevant for early identification of individuals at risk of VC and for informing therapeutic strategies.

Care of adolescents and young adults with diabetes - much more than transitional care: a personal view.

There is increasing recognition that type 1 diabetes mellitus (T1DM) acquired in childhood and adolescence requires a sophisticated approach that facilitates better self-management through adherence to generic principles in managing chronic disease in this age group, allied to the complex clinical needs of managing T1DM and related conditions. Transitional care should be seen as a process over time supported by both paediatric and adult diabetologists within a multidisciplinary team, given the complementary skills that can be brought to bear. Undoubtedly, there is a need for more effective training of all healthcare professionals working in this service. However, the accumulation of older teenagers over time and new diagnoses in those aged 19 years or more confirms that a new paradigm is necessary for the successful care of young adults beyond transitional care. Traditional clinical models will often not work for those in employment and higher education, with evidence that ongoing engagement following transfer to adult services often ceases. The alarming evidence of progressive complications in T1DM of longer duration in patients under the age of 40 years is a wake-up call to transform the care of this most vulnerable group.

Human uraemic serum displays calcific potential in vitro that increases with advancing chronic kidney disease.

Vascular calcification (VC) strongly correlates with declining renal function and contributes to the high morbidity and mortality of patients with CKD (chronic kidney disease). It is closely regulated by circulating factors but little is known about the capacity of serum from patients to induce calcification outside the disease setting, which we now define as the calcific potential of serum. We have therefore examined the ability of serum from age- and sex-matched subjects with and without advancing CKD to induce calcification of cultured SMCs (smooth muscle cells). Samples from patients with CKD induced significant calcification compared with controls. More importantly, samples from patients on haemodialysis induced significantly higher calcification than those with moderate or advanced CKD. The calcification induced by the latter two but not those on haemodialysis could be enhanced with calcium chloride and ß-GP (ß-glycerophosphate). A positive correlation was evident between measured serum creatinine, phosphate, PTH (parathyroid hormone), OPG (osteoprotegerin) and the degree of calcification in vitro. eGFR (estimated glomerular filtration rate), DBP (diastolic blood pressure), haemoglobin and serum albumin correlated negatively. Stepwise multivariate analysis of log-transformed calcific potential data highlighted serum creatinine, albumin and OPG as significant predictors, explaining approximately 50% of the variation. Thus, other regulators, either not investigated or as yet unidentified, may contribute to the calcification potential of serum in vitro. Furthermore, uraemic serum can induce graded calcification outside of the disease milieu that reflects the degree of kidney impairment in vivo. These findings could have important clinical relevance in terms of developing novel diagnostic and/or therapeutic strategies for subjects with CKD.

Managing type 1 diabetes in frailty.

Managing type 1 diabetes in frail elderly people can be logistically challenging, particularly for those living alone. District nurse visits are unpredictable and coincide poorly with meal time insulin regimes. Elderly people, particularly those with dementia, have variable oral intake and activity. For some, poor glycaemic control leads to frequent and prolonged inpatient admissions. The use of technology, such as flash glucose monitoring, and the use of analogue insulins can be helpful in this setting. Increased monitoring enables more accurate titration of insulin doses and the information can be accessed by healthcare professionals and carers remotely. Longer lasting analogue insulins allow for a greater margin of error in the timing of insulin administration.

Management of Hypertension in Patients With Diabetic Kidney Disease: Summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2021.

Diabetic kidney disease (DKD) accounts for >40% cases of chronic kidney disease (CKD) globally. Hypertension is a major risk factor for progression of DKD and the high incidence of cardiovascular disease and mortality in these people. Meticulous management of hypertension is therefore crucial to slow down the progression of DKD and reduce cardiovascular risk. Randomized controlled trial evidence differs in type 1 and type 2 diabetes and in different stages of DKD in terms of target blood pressure (BP). Renin-angiotensin blocking agents reduce progression of DKD and cardiovascular events in both type 1 and type 2 diabetes, albeit differently according to the stage of CKD. There is emerging evidence for the benefit of sodium glucose cotransporter 2, nonsteroidal selective mineralocorticoid antagonists, and endothelin-A receptor antagonists in slowing progression and reducing cardiovascular events in DKD. This UK guideline, developed jointly by diabetologists and nephrologists, has reviewed all available current evidence regarding the management of hypertension in DKD to produce a set of comprehensive individualized recommendations for BP control and the use of antihypertensive agents according to age, type of diabetes, and stage of CKD (https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdf). A succinct summary of the guideline, including an infographic, is presented here.

Association of British Clinical Diabetologists (ABCD) and Diabetes UK joint position statement and recommendations for non-diabetes specialists on the use of sodium glucose co-transporter 2 inhibitors in people with type 2 diabetes (January 2021).

Sodium glucose co-transporter 2 (SGLT2) inhibitors are now an established class of medications for the treatment of type 2 diabetes (T2D), no longer reserved for use by specialists in diabetes. They are being used increasingly for their cardiac and renal benefits by primary care, cardiology and renal teams for indications in parallel with diabetes care as part of holistic management. This guidance provides essential information on SGLT therapy, including the main advantages and the important risks of which healthcare professionals should be aware.

Holistic review of people with diabetes and chronic kidney disease reveals important multimorbidity and unmet clinical need: The ENHIDE diabetes renal telehealth pilot study.

Diabetes and kidney disease commonly coexist and management is complex given frequent additional comorbidity. The East and North Herts Institute of Diabetes and Endocrinology (ENHIDE) renal diabetes telehealth project examined the feasibility of data extraction from primary care records for virtual consultant review as a prelude to a telehealth case-based discussion with primary care teams. Data extraction identified 2,356 cases from 16 general practices, of which 14 took part in a skype telehealth case-based discussion session. The service was well received by primary care as a workable means of delivering patient care. In addition, significant unmet clinical needs were identified with opportunities to empower patient self-management of acute metabolic and foot issues, and better coordination of care between specialist diabetes and renal teams. The increasing clinical burden in all care settings and the commitment in the NHS plan for wider use of digital healthcare and streamlining of outpatient care highlight the need for service reconfiguration.

Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy.

Diabetic nephropathy is traditionally considered to be a primarily glomerular disease, although this contention has recently been challenged. Early tubular injury has been reported in patients with diabetes mellitus whose glomerular function is intact. Chronic hypoxia of the tubulointerstitium has been recognized as a mechanism of progression that is common to many renal diseases. The hypoxic milieu in early-stage diabetic nephropathy is aggravated by manifestations of chronic hyperglycemia-abnormalities of red blood cells, oxidative stress, sympathetic denervation of the kidney due to autonomic neuropathy, and diabetes-mellitus-induced tubular apoptosis; as such, tubulointerstitial hypoxia in diabetes mellitus might be an important early event. Chronic hypoxia could have a dominant pathogenic role in diabetic nephropathy, not only in promoting progression but also during initiation of the condition. Early loss of tubular and peritubular cells reduces production of 1,25-dihydroxyvitamin D3 and erythropoietin, which, together with dysfunction of their receptors caused by the diabetic state, diminishes the local trophic effects of the hormones. This diminution could further compromise the functional and structural integrity of the parenchyma and contribute to the gradual decline of renal function.

The conflict between specialist diabetes services and acute-general internal medicine for consultant diabetologists in the UK in 2006.

An online survey of consultant diabetologists in the UK examined the interface between specialist services and acute-general internal medicine (acute-GIM). Out of 592 consultants, 289 (49%) responded. Of these, 94% contributed to acute-GIM, devoting equivalent time to acute-GIM and specialist diabetes services. Of the respondents, 10% provided a single-handed specialist service and 78% provided endocrine services. The survey found the input to acute-GIM was increasing, partly because other specialties were opting out. The increased commitment to acute-GIM compromised specialist diabetes activity through reduced consultant and training-grade time for outpatient activity and service development. The shift to primary care of chronic disease led to further conflict between acute-GIM and delivery of a specialist service, given the current systems for provision of consultant-led care. The large number of specialist trainees in diabetes and endocrinology will require innovative commissioning mechanisms that reflect the need to sustain and develop specialist diabetes and endocrine care in the appropriate settings as well as the continued input in acute trusts for acute-GIM.

A new integrated care pathway for ambulance attended severe hypoglycaemia in the East of England: The Eastern Academic Health Science Network (EAHSN) model.

AIMS: We developed a new clinical integrated pathway linking a regional Ambulance Trust with a severe hypoglycaemia (SH) prevention team. We present clinical data from the first 2000 emergency calls taken through this new clinical pathway in the East of England. METHODS: SH patients attended by Ambulance crew receive written information on SH avoidance, and are contacted for further education through a new regional SH prevention team. All patients are contacted unless they actively decline. RESULTS: Median age (IQR) was 67 (50-80) years, 23.6% of calls were for patients over 80years old, and patients more than 90years old were more common than 20-25year olds in this population. Most calls were for patients (84.9%) who were insulin treated, even those over 80years (75%). One - third of patients attended after a call were unconscious on attendance. 5.6% of patients in this call population had 3 or more ambulance call outs, and they generated 17.6% of all calls. In total, 728 episodes (36.4%) were repeat calls. Insulin related events were clinically more severe than oral hypoglycaemic related events. Patients conveyed to hospitals (13.8%) were significantly older, with poorer recovery in biochemical hypoglycaemia after ambulance crew attendance. Only 19 (1%) opted out of further contact. Patients were contacted by the SH prevention team after a median 3 (0-6) days. The most common patient self - reported cause for their SH episode was related to perceived errors in insulin management (31.4%). CONCLUSIONS: This new clinical service is simple, acceptable to patients, and a translatable model for prevention of recurrent SH in this largely elderly insulin treated SH population.

Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/ GEM640.

Targeting apoptosis control provides a novel therapeutic approach to the treatment of cancer and other proliferative disorders. We summarize the evidence for apoptosis deregulation in cancer and describe the pivotal role of XIAP, the X-linked Inhibitor-of-APoptosis. XIAP is the predominant inhibitor of caspases 3, 7 and 9 in cells, which suppresses the programmed cell death effector capability of these proteases. Evidence is presented validating XIAP as a cancer target. The inhibition or downregulation of XIAP in cancer cells lowers the apoptotic threshold, thereby inducing cell death and/or enhancing the cytotoxic action of chemotherapeutic agents. We describe the development of AEG35156 (also named GEM640), a second generation antisense compound targeting XIAP, from concept to in vivo preclinical proof-of-principle studies, through formal toxicology, and to a phase 1 clinical trial in cancer patients.

Drug therapy for prevention of cardiovascular disease--should surrogate measures be abandoned?

It has been suggested that the most effective method of reducing cardiovascular disease (CVD) is to define overall CVD risk and apply fixed doses of anti-hypertensive, hypolipidaemic and anti-platelet therapies, using the evidence base from clinical outcome studies. Such studies have examined large numbers of patients with a wide representation of subgroups and demon-Welwyn strated equivalent benefits in all subsets. In so doing, there may be over-interpretation of the data leading to large-scale applicability of the findings to individuals who were not genuinely represented in the study populations. Most lipid-lowering studies have been unable to consider the possibility that optimal correction of dyslipidaemia would have been more effective than the use of a fixed dose of statins. Studies of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockade have produced contradictory findings regarding unique non-hypotensive beneficial CVD effects, and suboptimal control of mild hypertension was a frequent finding in the study populations. Scrutiny of concomitant therapy in studies that focus on a particular issue such as LDL (low-density lipoprotein) cholesterol or blood pressure supports the notion that benefits from the agent may be attenuated by other drugs. Widespread application of fixed doses of all these agents to at-risk cases will increase the incidence of inappropriate use and side effects. Clinical experience with modulators of the renin-angiotensin system in hypertensive diabetic renal disease confirms reduced efficacy, and more frequent deterioration of renal function than observed in clinical trials. Measurement of individual biomedical CVD risk factors along with overall risk estimation should continue to be the mainstay of clinical practice. This will allow appropriate case selection for different agents, optimisation of dosage or better assessment of compliance where treatment is less efficacious, and monitoring for adverse effects of therapy. Pragmatic individualisation of care should remain the basis for treating asymptomatic CVD risk factors.