Journal Watch

Glyburide versus metformin and their combination for the treatment of gestational diabetes mellitus

Zohar Nachum et al. Diabetes Care. DOI: https://doi.org/10.2337/dc16-2307

Glibenclamide (or Glyburide as it is known in the US) is recommended by the 2015 NICE guidance for women with gestational diabetes who are either intolerant of Metformin or decline insulin. Despite this recommendation, its use is often avoided either due to clinical concerns about oral agents in pregnancy or its efficacy. This study examined both the efficacy and safety of the drug in comparison with, and as an addition to Metformin. Women with GDM at 13-33 weeks, poorly controlled with diet were randomised to either Metformin or Glyburide which were combined if monotherapy was insufficient. In the Glyburide group, drug failure occurred in 23% due to inadequate glycaemic control and 11% due to hypoglycaemia. For Metformin, lack of control in 28% and GI side effects in 2%. Combining the drugs reduced the requirement for insulin by 21%. There were no adverse obstetric or neonatal outcomes. Overall, the fact that this study showed comparable efficacy between the drugs along with reduced requirement for insulin suggest that Glyburide should be more actively considered with a possible advantage for Metformin over Glyburide as first-line therapy.

http://care.diabetesjournals.org/content/early/2017/01/10/dc16-2307.long

 

Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes

L. Kristensen et al. Diabetic Medicine. DOI: 10.1111/dme.13317

Hypoglycaemia is the most common complication of treatment for Type 1 Diabetes, usually resulting from a mismatch between the blood glucose and insulin profiles. Avoiding and treating nocturnal hypoglycaemia can be more challenging especially in patients with recurrent severe episodes due to hypo unawareness. Evidence suggests that the more predictable profiles of insulin analogues reduces hypoglycaemia, a fact acknowledged by NICE guidance for T1DM. This cross over study of insulin Detemir (Levemir)/ aspart (Novorapid) and human NPH/ human regular insulin in 72 patients used hourly venous blood sampling to obtain glucose profiles for 2 consecutive nights. Mean blood glucose levels were higher in the analogue group although fasting glucose was similar. Nocturnal hypoglycaemia was less common in the analogue group (16% v 41%) Overall, the study confirms the known benefit of analogues with regard to hypoglycaemia but also demonstrates the benefit of the nocturnal glucose profile although this was only achievable with invasive testing. Newer monitors such as the freestyle libre may enable more comprehensive profiles to be obtained in order to avoid nocturnal hypoglycaemia.

http://onlinelibrary.wiley.com/doi/10.1111/dme.13317/abstract

 

Safer insulin prescribing

NICE

This document is the latest from NICE regarding hypoglycaemia. It advises: 1 Clinicians should ensure that people with diabetes who are receiving insulin therapy are given information about awareness and management of hypoglycaemia. 2 People with diabetes who use insulin and who drive should be aware of the need to notify the DVLA. 3 Clinicians should be aware of ‘sick-day’ rules and should ensure that people with diabetes who are receiving insulin therapy are given information about these. 4 They note that several new insulin products have been launched, including high-strength, fixed combination and biosimilar insulins and clinicians should be aware of the differences between these products and ensure that patients receive appropriate training on their use. 5 People should be advised to only use insulin in the way they have been trained. Finally, it recommends that adults who are using insulin therapy should receive a patient information booklet and an ‘insulin passport’ (although in the text, a safety card is seen as equivalent to the cumbersome passport). None of this is rocket science….

 https://www.nice.org.uk/advice/ktt20

 

Managing glycaemia in older people with type 2 diabetes

Jason Gordon et al. Diabetes, Obesity and Metabolism. DOI: 10.1111/dom.12867

This study examines the health and economic outcomes of different therapeutic approaches in older patients with type 2 diabetes failing on metformin (M) monotherapy. The Clinical Practice Research Datalink (CPRD) database was used to identify 10,484 patients requiring escalation (addition or switch) to a second-line oral regimen from 01-01-2008 to 31-12-2014. Primary outcomes included time to first event (any event, myocardial infarction (MI), stroke, or composite of MI/stroke [major adverse cardiovascular event; MACE]) and total event rate. Health economic consequences were assessed using the CORE Diabetes Model (CDM). The majority of patients (42%) received a sulphonylurea (SU) as second-line treatment whilst 28% switched to SU monotherapy (28%). In multivariate adjusted analyses, total event rates for M + dipeptidyl peptidase-4 inhibitor (DPP-4) were significantly lower than M+SU for MACE (0.61, 95% confidence interval [CI]: 0.39–0.98), driven by a lower MI rate in the DPP-4 group (0.52, 95% CI: 0.27-0.99). Economic analyses estimated that M+DPP-4 was associated with the largest gain in health benefit. This study supports the use of DPP-4s in the elderly, where they are not only safe but cost-effective.

http://onlinelibrary.wiley.com/doi/10.1111/dom.12867/abstract

 

Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes

Marshall B. Elam et al. JAMA. DOI: 10.1001/jamacardio.2016.4828

There is no doubt that the ‘dyslipidaemia’ which fibrates partially reverse (low high density lipoprotein (HDL) cholesterol and increased triglycerides) is associated with adverse cardiovascular (CV) outcomes. The problem has been the difficulty in demonstrating that fibrate use reduces CV events. Dyslipidaemia is common in type 2 diabetes (as part of the ‘metabolic syndrome’), and so fibrates have been examined in two large diabetes CV outcomes studies – FIELD and the ACCORD lipid study. The latter investigated their use in addition to statins (as would be real-life practice) and both studies yielded negative results, aside from a possible reduction in progression of diabetic retinopathy. This publication presents data from a five-year passive follow-up of 4,644 patients who were treated in the original ACCORD lipid study. Only 4.3% of them continued on fenofibrate therapy and overall, the same neutral effect on CV events was seen. However, a reduction in CV outcomes in the subgroup of patients designated as having dyslipidaemia, as reported in the original trial, was maintained. Perhaps fibrates do have a role in this cohort?

http://jamanetwork.com/journals/jamacardiology/article-abstract/2594262

 

https://www.glycosmedia.com/11195-2/

Standards of medical care in diabetes – 2017: summary of revisions

Diabetes Care. DOI: https://doi.org/10.2337/dc17-S003

In stark contrast to guidelines from the National Institute for Health and Care Excellence (NICE), which in the case of type 2 diabetes took over 5 years to be updated, the American Diabetes Association (ADA) reviews its ‘Standards of Medical Care in Diabetes’ on an annual basis. It also sensibly provides a summary of the changes so that busy clinicians don’t need to trawl through the entire Diabetes Care supplement (134 pages). The changes are wide-ranging, from an inclusion of psychosocial aspects of therapy in all areas of diabetes care, to a discussion of evidence for diabetes screening in dental practice. More specific advice relates to periodic vitamin B12 assessment in patients taking metformin and less focus on ACE-inhibitors for the treatment of hypertension (thiazides and calcium channel-blockers are given equal prominence). Important from a clinical trial perspective is the redefinition of clinically significant hypoglycemia as a glucose level below 3.0 mmol/L (rather than 4.0mmol/L) and acknowledgement of the positive outcomes from recent cardiovascular studies of newer diabetes therapies. Well worth a read.

http://care.diabetesjournals.org/content/40/Supplement_1/S4

 

Exploring the characteristics of suboptimally controlled patients after 24 weeks of basal insulin treatment: an individualized approach to intensification

Kamlesh Khunti et al. Diabetes Research and Clinical Practice. DOI: http://dx.doi.org/10.1016/j.diabres.2016.11.028

The authors present a post hoc analysis of the SOLVE study. This was an industry-sponsored 24-week, international, observational study which examined 17,374 patients with type 2 diabetes (T2DM) inadequately controlled on oral antidiabetic drugs (OADs) who went on to receive once-daily insulin. Patients were divided according to the achieved HbA1c (above or below 7.0% [<53.0 mmol/mol] at their final assessment. The baseline characteristics which were independently associated with ‘suboptimal control’ included higher baseline HbA1c (odds ratio [95% confidence interval]: 1.56 [1.50;1.62]; p < 0.0001), body mass index (1.03 [1.02;1.04]; p < 0.0001), longer duration of diabetes (5–10 years: 1.44 [1.25;1.66]; >10 years: 1.44 [1.17;1.77]; p < 0.0001), and greater number of OADs (two OADs: 1.27 [1.12;1.44]; >2 OADs: 1.38 [1.14;1.66]; p = 0.0003). Unfortunately, this almost perfectly describes the typical phenotype of UK patients who are initiated on basal insulin. Worse still, apart from the HbA1c, it also describes the sort of patient who would receive insulin when the current NICE guidelines are followed. Perhaps basal insulin shouldn’t be the treatment of last resort.

http://www.diabetesresearchclinicalpractice.com/article/S0168-8227(16)31736-3/fulltext

 

Lack of evidence to guide deprescribing of antihyperglycemics: a systematic review

Cody D. Black et al. Diabetes Therapy. DOI: 10.1007/s13300-016-0220-9

This is an interesting area which, I suspect, many clinicians have not given a great deal of consideration (I admit that I hadn’t). The authors begin by highlighting that good clinical management of type 2 diabetes (T2DM) recognises the risk of hypoglycaemia in frail and elderly patients and the implication that this will involve withdrawal of antidiabetic drugs in many cases (they term this ‘deprescribing’). They then go on examine evidence from all studies evaluating the effects of deprescribing in older adults with T2DM, searching MEDLINE, EMBASE, and the Cochrane Library. They managed to identify only two controlled before-and-after studies which were both ‘of very low quality’. One study found that an educational intervention decreased glibenclamide use while not compromising glucose control. The other reported that cessation of antihyperglycemics in elderly nursing home patients resulted in a non-significant increase in HbA1C. No significant change in hypoglycemia rate was reported but only one study had this as an outcome measure. The manuscript has essentially identified an evidence-free zone, which researchers should be encouraged to fill.

http://link.springer.com/article/10.1007%2Fs13300-016-0220-9

 

Second line initiation of insulin compared with DPP-4 inhibitors after metformin monotherapy

Thomas Nyström et al. Diabetes Research and Clinical Practice. DOI: http://dx.doi.org/10.1016/j.diabres.2016.12.004

The progressive nature of T2DM ensures that drug therapy requires regular review and escalation. It is widely accepted by all international guidelines that Metformin should be used first line but after this, individualised treatment choices should be considered. The last few years have resulted in a plethora of drug classes with most health care professionals using insulin after oral failure. Cardiovascular outcome studies have shown the DPP4 inhibitors (gliptins) to be safe whilst at the same time others have shown that tight control using insulin may actually increase mortality possibly due to an increased incidence of hypoglycaemia. This Swedish study compared the risk of all-cause mortality and severe hypoglycaemia with patients started on either insulin or a gliptin after Metformin. The population was older (mean age 65) and had significant co-morbidities including a high incidence of established macrovascular disease. Insulin treated patients had a higher risk of mortality and severe hypoglycaemia than those on a gliptin. The cause for the increased mortality is not clear but the incidence of hypoglycaemia is probably relevant.

http://www.diabetesresearchclinicalpractice.com/article/S0168-8227(16)30442-9/fulltext

 

Lowest glucose variability and hypoglycemia are observed with the combination of a GLP-1 Receptor agonist and basal insulin (VARIATION study)

Harpreet S. Bajaj et al. Diabetes Care. DOI: https://doi.org/10.2337/dc16-1582

Glucose variability has been identified as a predictor of hypoglycemia and has been found to be related to intensive care unit mortality. Other evidence suggests a link between it and micro and macrovascular complications of diabetes as well as being predictive of severe hypoglycaemia in T1DM and non-severe hypoglycaemia in T2DM. Despite multiple available insulin regimes, it is unclear as to which will reduce glucose variability. This cohort study used continuous glucose monitoring (CGM) in patients with well controlled diabetes on a number of regimes including basal insulin and a GLP1 agonist, twice daily premixed insulin, basal bolus and basal insulin plus a variety of oral agents. The lowest glucose variability and incidence of hypoglycaemia was found in the group treated with basal insulin and a GLP1 agonist. This is likely to be due to the synergistic properties of this regime which target fasting and post prandial glucose excursions. The reduction in hypoglycaemia may contribute to emerging evidence regarding cardiovascular risk reduction with GLP1 analogues.

http://care.diabetesjournals.org/content/early/2016/12/01/dc16-1582

https://www.glycosmedia.com/11119-2/

Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials

Diabetes Care. DOI: 10.2337/dc16-2215

Hypoglycaemia is a complication of diabetes that raises concern with patients and health care providers. Despite this, the threshold for hypoglycaemia varies between patients and also within the same patient depending on their frequency and overall control (HbA1c). This position statement from the ADA and EASD seeks to clarify the definition and absolute glucose values constituting an episode of hypoglycaemia. Specifically, glucose values of <3.0mmol/l, measured via self-monitoring, continuous glucose monitoring or a laboratory sample. This value was chosen as it is unequivocally a value that does not occur under physiological conditions in non-diabetic individuals. A value of <2.8mmol/l was also considered following its link to increased mortality in the ACCORD and ORIGIN studies. Three levels of hypoglycaemia have been proposed – alert if <3.9mmol/l, <3.0 indicating serious or clinically significant hypoglycaemia and severe in the presence of cognitive impairment or requiring external assistance for recovery.  It is also proposed that only values of <3.0mmol/l be reported in clinical trials, rather than readings <3.9mmol/l.

http://care.diabetesjournals.org/content/diacare/early/2016/11/09/dc16-2215.full.pdf

 

HbA1c and the prediction of type 2 diabetes in children and adults

Pavithra Vijayakumar et al. Diabetes Care. DOI: https://doi.org/10.2337/dc16-1358

It is recognised that Type 2 diabetes is no longer a condition only affecting older people with increasing number of patients being diagnosed in childhood, especially in those belonging to high risk populations. Whilst most guidelines use HbA1c as a diagnostic tool for T2DM, this has not been validated in children, an issue addressed in this paper which examined glycaemic thresholds in American Indian children using HbA1c, fasting and 2hour post load glucose. Stratifying patients into T2DM (HbA1c>6.5%, FPG>7.0 and 2hr glucose >11.1mmol/l), 2095 children without diabetes aged 10-19 underwent long term review.  During long-term follow-up of children and adolescents who did not initially have diabetes, the incidence rate of subsequent diabetes was fourfold (in boys) as high and more than sevenfold (in girls) as high in those with HbA_1c ≥5.7% as in those with HbA_1c ≤5.3%. Identifying the risk of T2DM was not different whether HbA1c, FPG or 2hr glucose was used. The study suggests that HbA1c is a predictor of risk in children and can be used as a tool to target lifestyle intervention.

http://care.diabetesjournals.org/content/early/2016/11/02/dc16-1358

 

Gastric bypass surgery reveals independency of obesity and diabetes melitus type 2

Mogens Fenge et al. BMC Endocrine Disorders. DOI: 10.1186/s12902-016-0140-8

Roux-en-Y gastric bypass surgery (RYGB) is the most effective form of bariatric surgery with patients permanently losing approximately 40% of their body weight whilst in patients with pre-existing T2DM, remission may occur in 40-80%. However, this remission tends to occur within days of the surgery often before any weight loss has occurred. This study examined weight loss trajectories in groups of patients who were non-diabetic, diabetic pre- and post-surgery, and those whose diabetes went into remission post-surgery. Weight loss rates varied significantly between the groups with up to 11 sub populations identified which were felt to represent different physiological states. These states were presumed to be due to a combination of genetic predisposition and the changed anatomy with further variability conferred by alterations to gut flora and hormones. Patients who lost a significant amount of weight tended to be more likely to go into remission from their diabetes probably due to improved insulin sensitivity which remained even if they regained some weight. Overall, this rather complex paper does not significantly advance understanding of the heterogeneity of response to bariatric surgery.

http://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-016-0140-8

 

TRENDS in medication use in patients with type 2 diabetes mellitus a long-term view of real world treatment between 2000 and 2015

Authors: Higgins V, Piercy J, Roughley A, Milligan G, Leith A, Siddall J, Benford M

https://www.dovepress.com/article_29807.t61857047

The authors collected data on type 2 diabetes (T2DM) prescribing between 2000 and 2015 in the US and five EU countries, including the UK. Clinicians completed patient record forms for their next 10 patients allowing capture of change over time in therapy usage, time to insulin and HbA1c. Data from 70,657 patients showed treatment patterns changed and the number of agents prescribed per patient increased over time, as did HbA1c levels at which physicians would introduce insulin. HbA1c improved during 2000–2008 but was stable thereafter. This type of report is often used to snipe at the use of newer, expensive anti-diabetes therapies (ADTs) and argue for a return to metformin, sulphonylurea and human insulin. However, interpretation of these real-life data is complex. It is hardly surprising that the shift of T2DM management into primary care, over a period when three new oral ADT classes were launched, has led to more complex oral regimes. It is also of note that clinicians have much higher thresholds for insulin initiation than any current guidelines. The authors are right to recommend further investigation.

https://www.dovepress.com/article_29807.t61857047

 

Tackling variation in diabetes care

This report is published by the All-Party Parliamentary Group for Diabetes and so will hopefully carry some weight with the Clinical Commissioning Groups in England and Health Boards in Wales. It highlights that the quality of care someone with diabetes receives, and presumably the outcomes they achieve, depends on where they live. The key message is that good diabetes care is possible and the task is to make it happen everywhere.

For me, the highlights are:

.        Training for healthcare professionals (HCPs) should be increased to allow them to have the knowledge and skills to give accurate advice i.e. an admission that T2DM cannot be appropriately managed by HCPs without specialist knowledge.

• A focus on structured education, which includes one-to-one advice (i.e. one group-sized education programme doesn’t fit all) and the need for psychological support.
• The need for the NHS to provide access to new technologies. The report highlights that ‘muddled funding processes make accessing technology difficult even when someone satisfies the NICE criteria for it’.

Let’s hope that this report helps push diabetes higher up the NHS priority list.

https://diabetes-appg.co.uk/2016/11/23/tackling-variation-in-diabetes-care/

 

https://www.glycosmedia.com/11021-2/

Clinical inertia to insulin initiation and intensification in the UK: A focused literature review

Kamlesh Khunti and David Millar-Jones. Primary Care Diabetes. DOI: http://dx.doi.org/10.1016/j.pcd.2016.09.003

The benefit of glycaemic control in T2DM has been shown in the UKPDS study where reduced microvascular disease after 10 years and macrovascular disease in the decade after were shown in the intensive control arm. This has also been shown in other studies including VADT. Furthermore, the progressive nature of T2DM due to β cell failure is well recognised as is the requirement to monitor the effect of hypoglycaemic agents and intensify treatment when necessary. This is reinforced in the 2015 NICE guidance with an HbA1c of 7.5% being set as an intensification threshold. Patients are often reluctant to intensify their treatment, especially when insulin is introduced including changes to insulin regime and number of injections. The UK is one of the worse countries in Europe for this ‘clinical inertia’ as shown in the SOLVE study where the UK cohort had a mean HbA1c of 9.8% v 8.9% in the global population at insulin initiation despite a shorter duration of disease. Reasons for this inertia include fear of injections and hypoglycaemia as well as lack of confidence by clinicians – given that routine management is moving into primary care.

http://www.primary-care-diabetes.com/article/S1751-9918(16)30099-7/fulltext

 

Bariatric surgery in women of childbearing age, timing between an operation and birth, and associated perinatal complications

Brodie Parent et al. JAMA Surgery. DOI: 10.1001/jamasurg.2016.3621

The rise in obesity has led to increasing numbers of bariatric procedures being performed in women of child bearing age. Obesity has a significant impact on pregnancy, being associated with fetal macrosomia, hypertension and gestational diabetes. Given the metabolic changes that happen after surgery, patients are advised not to become pregnant for 2 years after the procedure especially as this time of rapid weight loss and metabolic changes can result in nutritional deficiencies. This retrospective study looked at the relationship between perinatal outcomes in pregnancies occurring shortly after surgery. Compared with women without a history of surgery, ‘post-operative mothers’ had a higher incidence of prematurity, low Apgar scores and admissions to NICU. Women whose pregnancy occurred less than 2 years after surgery had a higher rate of these complications than those whose pregnancies occurred more than 4 years after surgery. Given the improved fertility associated with weight loss, the need to postpone pregnancy for some time after a bariatric procedure should be reinforced pre-operatively.

http://jamanetwork.com/journals/jamasurgery/fullarticle/2569812

 

Attitudes towards insulin initiation in type 2 diabetes patients among healthcare providers: a survey research

Javier Escalada et al. Diabetes Research and Clinical Practice. DOI: http://dx.doi.org/10.1016/j.diabres.2016.10.003

‘Clinical inertia’ is a buzz phrase in diabetes, highlighting slow escalation of hypoglycaemic therapy in patients with poorly controlled type 2 diabetes (T2DM). Published studies typically assess routinely collected data and these are nowhere near as robust as clinicians are led to believe. For example, whilst databases allow for assessment of HbA1c at the time of initiation of a new class of hypoglycaemic agent, they do not capture treatment escalation within a class. Given that the first two default therapies for T2DM (metformin and sulphonylureas) have several dose steps (up to ten), this is a major limitation. One thing that is not in doubt is that insulin initiation occurs at much higher HbA1c levels than are recommended in any guideline (typically 86 mmol/mol [10%] in the UK). This observational study from Spain highlights that GPs and non-specialists delay insulin starts for longer than endocrinologists and initiate at higher HbA1c levels – no surprises here. However, it also shows that only a minority of endocrinologists follow guidelines for insulin initiation. This may imply lack of ‘buy-in’ to the treatment targets rather than inertia?

http://www.diabetesresearchclinicalpractice.com/article/S0168-8227(16)30503-4/fulltext

 

Mechanistic modeling of hemoglobin glycation and red blood cell kinetics enables personalized diabetes monitoring

Roy Malka et al. Science Translational Medicine. DOI: 10.1126/scitranslmed.aaf9304

Practicing clinicians are familiar with the concept of a ‘normal range’ when they receive the results of investigations. Almost all routinely requested biochemistry tests have variation which is clinically acceptable and this includes the haemoglobin A1c (HbA1c) …. until a patient is diagnosed with diabetes. At this point, variability ceases to exist and one value applies to all. The HbA1c target is 6.5% (48mmol/mol) or 7.5% (58mmol/mol) or whatever is individualised for the patient but it is never a range between ‘X’ and ‘Y’. This is clearly a nonsense. This complex mathematical paper provides theoretical support for this contention. The authors examine the relationship between HbA1c and average blood glucose concentration and report substantial glucose-independent variation in HbA1c that limits its precision. They then combined a mechanistic mathematical model of hemoglobin glycation and red blood cell kinetics with large sets of within-patient glucose measurements. Mean red blood cell age was found to explain all the glucose-independent variation. It is unlikely that this methodology will be introduced into clinical practice but hopefully it will make clinicians think about HbA1c targets.

http://stm.sciencemag.org/content/8/359/359ra130.full

 

Current perspectives on cardiovascular outcome trials in diabetes

Oliver Schnell et al. Cardiovascular Diabetology. DOI: 10.1186/s12933-016-0456-8

There are now three published cardiovascular outcome trials (CVOTs) which have demonstrated superiority of glucose-lowering therapies versus placebo. The first examined the SGLT-2 inhibitor, empagliflozin, whilst the latter two used the GLP-1 receptor agonists, liraglutide and semaglutide. This review highlights some of the issues that remain unanswered. The authors point out that components of the primary end-point have different aetiologies (e.g. thrombosis for myocardial infarction, arrhythmias for CV death) and also focus on the need to closely examine heart failure. They highlight the difficulty of extrapolating results from high-risk CV patients included in these studies to the general T2DM population. The relatively short duration of the studies is noted, with the suggestion that this could be addressed by the use of routinely collected data. The lack of active comparators is seen as a weakness and the authors suggest that more detailed analysis of microvascular complications should be included in future protocols. Finally, they observe that the most commonly used hypoglycaemic agents, metformin and sulphonylureas, have not be exposed to the scrutiny of a CVOT – and probably never will be.

http://cardiab.biomedcentral.com/articles/10.1186/s12933-016-0456-8

https://www.glycosmedia.com/10951-2/

Dipeptidyl peptidase-4 inhibitors and cardiovascular risks in patients with pre-existing heart failure

Shuo-Ming Ou et al. Heart. Doi:10.1136/heartjnl-2016-309687

Launched 9 years ago, the Dipeptidyl peptidase-4 inhibitors (gliptins) have rapidly found favour amongst clinicians treating Type 2 diabetes and, following NICE guidance can be positioned as second line agents after Metformin. Recent cardiovascular studies have shown them to be generally safe although Saxagliptin was associated with an unexpected 27% increase in admissions to hospital from heart failure, an issue not demonstrated with other gliptins. This insurance database Taiwanese study looked at the impact of gliptins on high risk patients with established heart failure. Reassuringly, the risk of hospitalisation from heart failure was not increased. Interestingly, the risks of mortality and the combination of MI and ischaemic stroke were lower for patients receiving DPP-4 inhibitors although the mechanism for this remains unclear. Overall, this and other studies suggest that the class is safe although, in patients with normal renal function, an SGLT2 may be a more appropriate option especially for patients where heart failure may be an issue.

http://heart.bmj.com/content/early/2016/09/19/heartjnl-2016-309687.abstract

 

Follow-up of blood-pressure lowering and glucose control in Type 2 Diabetes

Zoungas et al. NEJM. Doi: 10.1056/NEJMoa1407963

After completion of DCCT (young patients with T1DM), UKPDS (newly diagnosed T2 patients) studies, post-trial or legacy results have recently been published. In these legacy studies, the groups previously randomised to intensive glucose control continued to show a reduction in micro and macrovascular disease – in UKPDS glucose control became significant. In the ADVANCE study, a single tablet of Perindopril-Indapamide reduced the risk of macrovascular disease whilst intensive glucose lowering reduced the risk of micro and macrovascular disease, the latter primarily due to its impact on nephropathy in this latest 6 year follow up of the ADVANCE patients. In the blood pressure lowering group, the risk of death from a cardiovascular event, although attenuated was still significant whilst there was no evidence that intensive glucose lowering had a long term impact on macrovascular events. Whilst this does seem to differ from UKPDS legacy, in the ADVANCE study, the patients had a lower baseline. Although this fell during the study, it did not fall further afterwards unlike the UKPDS patients. Furthermore, more effective cardiovascular prevention (including lower lipid targets) may have added to the lack of effect on glucose lowering long term.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1407963

 

Early diabetes screening in women with previous gestational diabetes: a new insight

Aline Nabuco et al. Diabetology & Metabolic Syndrome. Doi: 10.1186/s13098-016-0172-2

Gestational diabetes (GDM) is a risk factor for the development of Type 2 diabetes with approximately 40-50% of patients developing the condition within 10 years of delivery. Although GDM usually resolves post-partum, NICE recommends screening for T2DM approximately 6 weeks after delivery despite the fact that the oral glucose tolerance test (OGTT) is a more sensitive method. Whilst 6 weeks post-partum seems to have been chosen as it fits in with other post-natal testing, this study examined the glucose tolerance of GDM patients 48-72 hours post-partum and its correlation with a 6 week OGTT. They found that fasting and 2 hour OGTT glucose levels of 4.3 and 7.2mmol/l respectively were optimal levels to screen for dysglycaemia after GDM complicated pregnancies and that the 2hour OGTT was more accurate than fasting glucose in predicting this. Whilst this study confirms the benefit of the OGTT in screening for T2DM, in the UK, recommendations from NICE moving towards fasting glucose and HbA1c may miss significant numbers of at risk women.

http://dmsjournal.biomedcentral.com/articles/10.1186/s13098-016-0172-2

 

Patterns of anti-diabetic medication use in patients with T2DM in England and Wales

Preeti Datta-Nemdharry et al. Pharmacoepidemiology and Drug Safety. Doi: 10.1002/pds.4092

In 2009 the National Institute for Health and Care Excellence (NICE) produced guidelines for management of hyperglycaemia in type 2 diabetes (T2DM). These could be distilled down to a preferred sequence of metformin, sulphonylurea and (human) basal insulin with options at each treatment escalation. This study sought to examine how well the guidance was followed in England & Wales between 2000-12 using data from the Clinical Practice Research Datalink. 123,671 patients, 56% males, 95% aged over 40 years and 79% with at least one recorded HbA1c level were included. Metformin was first prescription for 80% of patients (mean HbA1c 71.4 mmol/mol [8.68%]) whilst 16% received sulphonylurea first-line (mean HbA1c 78.3 [9.31%]). Patients initially prescribed insulin had mean HbA1c 84.6 [9.89%]. The authors state that 78% patients were managed in line with NICE, ignoring the fact that most of the observation period pre-dated the recommendations from NICE and that prior to 2007 treatment options were limited (incretin agents were not available). Furthermore, levels of HbA1c at therapy initiations were much higher than NICE recommended.

http://onlinelibrary.wiley.com/doi/10.1002/pds.4092/abstract

 

Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease

Samuel Adamsson Eryd et al. BMJ. Doi: http://dx.doi.org/10.1136/bmj.i4070

 

Systolic blood pressure (SBP) targets for people with type 2 diabetes (T2DM) have become controversial with levels in US guidelines now set at 140mmHg, higher than was previously the case. This follows on from the ACCORD BP trial which failed to show any benefit from tight control of SBP (<120mmHg) versus standard treatment (~ 135mmHg). This is not the case in non-diabetics, however, where the SPRINT trial, showed that targeting SBP less than 120mmHg led to lower rates of cardiovascular disease (CVD) and all-cause death. This population based cohort study adds to the debate. It followed 187,106 Swedish T2DM patients aged less than 75 years for a mean of five years. Clinical events were obtained from hospital discharge and death registers and hazard ratios estimated for different levels of baseline SBP. The group with the lowest SBP (110-119 mm Hg) had a significantly lower risk of CVD than the reference group (130-139 mm Hg), implying that current targets are too high. One caution; this study cohort had no previous CVD, suggesting that targets need to be individualised.

http://www.bmj.com/content/354/bmj.i4070.long

 

https://www.glycosmedia.com/10949-2/

National Diabetic Foot Audit of England and Wales yields its first dividends

William Jeffcoate et al. Diabetic Medicine. Doi: 10.1111/dme.13191

Despite diabetes resulting in the largest cause of non-traumatic amputations, and the fact that it costs approximately £600m/ year (almost 1% of the NHS budget), it is often neglected despite NICE guidance. The quality of care provision across the UK has been examined in the first national diabetes foot audit which received data from 5000 people treated by 130 foot care teams. Of the 60% of participating commissioning organisations who could answer the questions about service structure, more than 40% of them did not have 3 of the NICE recommended systems for detecting and managing diabetic foot disease. 85% of people had foot checks within the last year, and whilst 30% of ulcer patients self-presented, more than 40% were not seen by the foot care service within 2 weeks. The longer the delay before being seen by the diabetic foot care team, the more likely were the foot ulcers to be severe. Patients who self-presented or who were seen by the specialist foot care service within two weeks of first assessment by another healthcare professional had higher rates of ulcer healing than those seen later. Despite demonstrating gaps in reporting and variation in patient care, this first audit provides a benchmark to aid service development including the reinforcement of structured care and rapid access to the specialist team.

http://onlinelibrary.wiley.com/doi/10.1111/dme.13191/abstract

 

Are there benefits for gestational diabetes mellitus in treating lower levels of hyperglycemia than standard recommendations?

Thi Hoang Lan Nguyen et al. Canadian Journal of Diabetes. Doi: http://dx.doi.org/10.1016/j.jcjd.2016.05.009

The complications of hyperglycaemia in pregnancy are well known. However, despite multiple guidelines, controversy still exists regarding the diagnostic threshold for gestational diabetes (GDM). This retrospective study reviewed outcomes in women with and without GDM. Criteria for diagnosis were stricter than current Association of Diabetes and Pregnancy Study Groups (IADPSG) guidelines and was diagnosed if fasting levels were greater than 5.0mmol/l or 2hr GTT level above 7.8mmol/l. Rates of macrosomia and pre-eclampsia were significantly higher in the group with GDM. Macrosomia, the need for insulin therapy or caesarean section and postpartum glucose intolerance predictors included pre-pregnancy body mass index, excessive gestational weight gain and OGTT screening results, although no specific threshold was found. These findings suggest a continuous association between adverse outcomes and maternal hyperglycemia and highlight the important role of maternal risk factors other than glycaemic results in the development of pregnancy-related complications. Milder forms of hyperglycemia that would not be identified by IADPSG guidelines may benefit from treatment. In summary however, this finding is similar to those from the much larger ACHOIS study so it is not clear what new evidence was provided in this paper.

http://www.canadianjournalofdiabetes.com/article/S1499-2671(16)30138-1/fulltext

 

The efficacy and safety of liraglutide as adjunct therapy to insulin in the treatment of type 1 diabetes (ADJUNCT ONE™)

ClinicalTrials.gov Identifier: NCT01836523

Liraglutide, an injectable glucagon-like peptide 1 receptor agonist (GLP-1RA) is a widely used therapy in type 2 diabetes with effective reduction of HbA1c combined with weight reduction and low risk of hypoglycaemia. This study examined the benefits of using it as an adjunct to therapy in patients with type 1 diabetes (T1DM). It was a 52-week, double-blind, treat-to-target trial involving 1,398 adults randomised 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin. HbA1c was modestly reduced (0.34–0.54%; 3.7–5.9 mmol/mol) from a mean baseline of 8.2% (66 mmol/mol), this being significant in the two higher liraglutide doses. Insulin doses were also reduced as was mean body weight, which was clinically significant at all liraglutide doses (2.2, 3.6 & 4.9Kg). Unfortunately, the rate of symptomatic hypoglycemia increased in all groups and hyperglycemia with ketosis increased significantly for liraglutide 1.8 mg with an event rate ratio of 2.22. Although there are data that liraglutide can smooth out glycaemic variability in T1DM patients, the results from this study mean it is unlikely to be licensed for this group of patients.

https://clinicaltrials.gov/ct2/show/NCT01836523?term=Liraglutide+as+Adjunct+Therapy+to+Insulin+in+the+Treatment+of+Type+1+Diabetes&rank=1

 

Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8)

Juan P Frías et al. The Lancet Diabetes & Endocrinology. Doi: http://dx.doi.org/10.1016/S2213-8587(16)30267-4

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) are hypoglycaemic drug classes which also reduce weight and improve cardiovascular (CV) outcomes. DURATION 8 examined the combination of exenatide (E: GLP-1RA) and dapagliflozin (D: SGLT2i) in 685 adults with type 2 diabetes inadequately controlled by metformin (mean HbA1c 9·3%; 78 mmol/mol). The primary endpoint was change in HbA1c from baseline to 28 weeks; various secondary endpoints included change in weight and systolic blood pressure. The reductions in HbA1c were −2·0% (E+D group), −1·6% (E only), and −1·4% (D only). E+D was significantly better than either component alone and this was also seen for all secondary efficacy endpoints. Adverse events were reported in 57% of E+D patients, 54% of E only patients and 52% of the D only group. No episodes of hypoglycaemia were reported. The authors conclude that co-initiation of the classes improves various glycaemic measures and CV risk and was well tolerated. Whether this equates to a synergistic benefit on CV outcomes requires additional long-term studies.

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(16)30267-4/fulltext

 

Intensification of diabetes therapy and time until a1c goal attainment among patients with newly diagnosed type 2 diabetes who fail metformin monotherapy within a large integrated health system

Kevin M. Pantalone et al. Diabetes Care. Doi: http://dx.doi.org/10.2337/dc16-0227

This manuscript reports United States data concerning clinical inertia, defined as ‘delay in the intensification of type 2 diabetes (T2DM) treatment among patients with poor glycemic control’. The electronic health record at the Cleveland Clinic identified patients with newly diagnosed T2DM between 2005 and 2013 who failed to reach HbA1c goal after 3 months of metformin monotherapy. Analysis was used to compare the time until HbA1c goal attainment in patients who received intensification of therapy within 6 months of metformin failure versus later intensification. The analysis was performed for HbA1c goals of (1) 7% (53mmol/mol), (2) 7.5% (58mmol/mol), and (3) 8% (64mmol/mol).

The probability of undergoing early intensification was greatest in the highest HbA1c category but was only 62%, 69%, and 72% of patients going from lowest to highest goal. The time to HbA1c goal attainment was shorter among patients who received early intensification, whatever their HbA1c goal.

Given the profile of modern second-line therapies for T2DM (regarding risk of hypoglycaemia and weight-gain), there can be little excuse for delays in intensification in patients sub-optimally controlled on metformin.

http://care.diabetesjournals.org/content/early/2016/07/06/dc16-0227

Risk factors for spontaneously self-reported postprandial hypoglycemia after bariatric surgery

Monica Nannipieri et al. Journal of Clinical Endocrinology & Metabolism. Doi: http://dx.doi.org/10.1210/jc.2016-1143

Bariatric surgery is often seen as a quick and easy solution for obesity, especially as surgical techniques have developed with techniques varying from causing malabsorption (such as Roux-en-Y bypass – RYGB) to those reducing stomach size (gastric band and laparoscopic sleeve gastrectomy – LSG). However, many of these techniques result in significant post-operative symptoms including post prandial hypoglycaemia (PPHG) which can be disabling. As a result, patient selection for bariatric surgery is important in order to achieve the best outcomes as is post-operative follow up. This study examined some of the predictive indicators for PPHG in self-reporting groups of patients following both procedures using glucose tolerance tests in an attempt to reproduce it. In patients self-reporting PPHG following both procedures, lower pre-surgery fasting and post prandial glucose levels, higher insulin sensitivity and better β cell function were found to be significant predictors of PPHG or, put another way, the more insulin resistant the patient is pre-operatively, the less likely they are to suffer PPHG.

http://press.endocrine.org/doi/abs/10.1210/jc.2016-1143#sthash.LmNn0XXP.dpuf

 

Distinct clinical characteristics and therapeutic modalities for diabetic ketoacidosis in type 1 and type 2 diabetes mellitus

Yuji Kamata et al. Journal of Diabetes and Its Complications. Doi: http://dx.doi.org/10.1016/j.jdiacomp.2016.06.023

Diabetic ketoacidosis (DKA) is a relatively common complication of Type 1 diabetes (T1DM). However, a combination of increasing insulin deficiency and insulin resistance can result in DKA in patients with T2DM often in older, non-white patients sometimes presenting with diabetes for the first time and as a result, can have a higher mortality than in T1DM. Although the basic treatment is the same whatever the underlying cause (fluids, potassium and insulin), the exact clinical characteristics of the patients and intensity of treatment is unclear and was therefore examined in this retrospective study which compared the clinical features and treatment of 127 T1 and 74 T2 patients who presented between 2001 and 2014. Whilst infections were the main trigger for DKA in T1DM, sugary drink consumption was the main precipitating cause in T2DM. The latter tended to have higher glucose levels on presentation with more serious renal dysfunction. T2 patients also required a higher insulin dose, larger fluid replacement volumes and greater potassium supplementation. Given this, perhaps specific guidelines should be developed for them. Although these patients tender to be sicker, the majority recover but specialist input is important when decisions about long term treatment are made as not all these patients will require insulin.

http://www.jdcjournal.com/article/S1056-8727(16)30252-5/abstract

 

Gastric bypass reduces symptoms and hormonal responses in hypoglycemia

Niclas Abrahamsson et al. Diabetes. Doi: http://dx.doi.org/10.2337/db16-0341

As well as causing weight loss by mechanical effects, gastric bypass surgery also has an impact on metabolic parameters, specifically its impact on gut and counter regulatory hormones. Commonly these patients also have lower glucose levels and frequent asymptomatic episodes of hypoglycaemia.  Using a hyperinsulinaemic, hypoglycaemic clamp this study subjected patients to hypoglycaemia (2.7mmol/l) pre and post procedure and examined symptoms, hormonal and autonomic nerve responses in 12 obese non diabetic patients. Post surgery, symptoms were attenuated and there were also marked reductions in glucagon, cortisol, catecholamines and sympathetic nervous response.  The rise in GLP-1 was also reduced post surgery. In summary, the study showed that gastric bypass surgery caused a reset in glucose homeostasis which reduces the body’s response to hypoglycaemia both metabolically and symptomatically. Given the potential for significant post operatives problems caused by hypoglycaemia, this study reinforces the need to select patients for bariatric surgery as well as arranging their long term follow up.

http://diabetes.diabetesjournals.org/content/early/2016/06/12/db16-0341

 

Long-term cognitive implications of intrauterine hyperglycemia in adolescent offspring of women with T1D (the EPICOM study)

Birgitte Bytoft et al. Diabetes Care. Doi: http://dx.doi.org/10.2337/dc16-0168

Pregnancy and diabetes are not good bed-fellows. Chose any unwanted outcome, both maternal and foetal, and its likelihood is increased by the presence of maternal hyperglycaemia. This study adds another downside to the extensive list. The EPICOM study is a prospectively followed cohort of women with type 1 diabetes (T1DM). In this study, the offspring of 277 participants had evaluation of cognitive function aged 13-19 years. Comparisons were made with a controls (N=301) taken from the background population. Study offspring scored lower in all intelligence indices: composite intelligence (95.7 vs. 100, P = 0.001), verbal intelligence (96.2 vs. 100, P = 0.004), nonverbal intelligence (96.4 vs. 100, P = 0.008), and composite memory (95.7 vs. 100, P = 0.001). A higher frequency also had parent-reported learning difficulties in primary school, implying that these differences can be clinically relevant. Perhaps the only positive outcome of the study was that there was no correlation between offspring cognitive function and maternal HbA1c so these data should not promote further reductions in HbA1c targets for T1DM patients contemplating pregnancy – the current levels are impossible for many women…

http://care.diabetesjournals.org/content/early/2016/05/23/dc16-0168

 

Dipeptidyl peptidase-4 inhibitors and bone metabolism: is vitamin D the link?

Barchetta et al. Acta Diabetologica. Doi: 10.1007/s00592-016-0882-9

The interaction between type 2 diabetes (T2DM) and bone metabolism was first highlighted by reports of increased risk of fracture in women taking the thiazolidinedione (TZD) rosiglitazone in the ADOPT study. This was a completely unexpected finding, which was subsequently found to be a class effect of the TZDs and is seen in both sexes. The reason for this side-effect remains unknown but it has led to new therapy classes for T2DM to be scrutinised for adverse events relating to bone and for investigation of their impact on bone metabolism. This publication examines serum 25(OH) vitamin D in 295 T2DM patients, 53% of whom were taking a DPP4-inhibitor. It reports significantly higher levels compared with patients taking other antidiabetic therapies (18.4 ± 10.7 vs. 14.9 ± 8.6 ng/ml, p = 0.004), an association which persisted after adjusting for major confounders. The authors suggest that this might explain ‘the positive effect of DPP-4 inhibitors on bone metabolism’; whether this equates to clinical benefit remains to be seen.

http://link.springer.com/article/10.1007%2Fs00592-016-0882-9

 

The genetic architecture of type 2 diabetes

Christian Fuchsberger et al. Nature. Doi:10.1038/nature18642

Diabetes was famously referred to as the ‘geneticist’s nightmare’ in 1976. Although familial clustering of diabetes was well known, the pattern of inheritance did not conform to that of a dominant or recessive trait. The potential for genetic dissection had been boosted by the identification of HLA genes in type 1 diabetes, cementing the long recognised clinical description of at least two distinct forms of disease. Then, during the 1990’s genes for monogenic forms of diabetes (termed MODY) were identified. But where are we with the genetic predisposition for type 2 diabetes (T2DM)? This manuscript suggests not a good place. The authors conclude that their massive genotyping endeavor does not support the idea that lower-frequency variants have a major role in predisposition to T2DM. Numerous small gene effects have previously been reported to predispose to T2DM but none of them have led to new therapies nor can they be used as predictive markers. Given the well-known environmental factors which predispose to T2DM, perhaps R&D funds would be better directed to their reversal rather than pursuing the nightmare?

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature18642.html

 

Long-term excess mortality associated with diabetes following acute myocardial infarction

O A Alabas et al. Journal of Epidemiology & Community Health. Doi:10.1136/jech-2016-207402

It is well known that type 2 diabetes is associated with an increased risk of cardiovascular disease and acute myocardial infarction (AMI) is an important manifestation of this. Indeed, fatal and non-fatal AMI is included in the primary composite end-point for the cardiovascular outcome studies, now mandated for all new diabetes medicines. This publication examines the long-term excess risk of death associated with diabetes following AMI using data from the MINAP study, based in the UK. Between 2003-13, there were more than 1.94 million person-years follow-up including 120 568 (17.1%) patients with diabetes. All-cause mortality was higher among patients with diabetes (35.8% vs 25.3%). After adjustment for age, sex and year of acute myocardial infarction, diabetes was associated with a significant 72% excess risk of death following ST elevation AMI (and 67% for Non-STEMI). Diabetes remained significantly associated with substantial excess mortality despite cumulative adjustment for comorbidity and cardiovascular treatments. These results provide an updated, UK confirmation of the importance of AMI in patients with diabetes, highlighting the potential benefits of antidiabetic agents which reduce this end-point.

http://jech.bmj.com/content/early/2016/06/15/jech-2016-207402.short

 

Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus

Kenneth Cusi et al. Annals of Internal Medicine. Doi:10.7326/M15-1774

Nonalcoholic fatty liver disease (NAFLD) is said to be reaching epidemic proportions worldwide and most patients with type 2 diabetes (T2DM) are thought to have this condition. Indeed, many T2DM patients are at risk of the more severe nonalcoholic steatohepatitis (NASH) even if they have normal liver aminotransferase levels. The argument goes that therapies for T2DM should be prioritized if they have a beneficial impact on NAFLD. This study examined 101 subjects with prediabetes or T2DM and biopsy-proven NASH. All were prescribed a hypocaloric diet and then randomly assigned to pioglitazone (45mg OD), or placebo for 18 months, followed by 18-month open-label pioglitazone. The primary outcome of improvement in liver histology was achieved in 58% and 51% had resolution of NASH. One of the difficulties in interpreting these studies is how to tease out the impact of improved glycaemic control from that of the specific drug. Having said that, some recent data suggest that sitagliptin was no more effective at reducing NAFLD than placebo. So, a come-back for pioglitazone? Perhaps it will be led by the gastroenterologists….

http://annals.org/article.aspx?articleid=2529686

 

Trends in hospital admissions for hypoglycaemia in England: a retrospective, observational study

Francesco Zaccardi et al. The Lancet Diabetes & Endocrinology. Doi: http://dx.doi.org/10.1016/S2213-8587(16)30091-2

The recent National Diabetes In-patient audit continues to show that rates of hypoglycaemia remain an issue both for patients in hospital and also as a reason for admission. However, given the education provided to patients at diagnosis and during follow up around hypoglycaemia management, the expectation would be that self-treatment should reduce admissions. Using the hospital episode statistics database, this retrospective study showed that 72% of the 101475 admissions over a 10-year period for hypoglycaemia occurred in patients aged over 60 with 18% having multiple admissions. Furthermore, over the 10 years, admissions for hypoglycaemia increased by 39% although when the increase in the prevalence of diabetes was taken into consideration, there was a reduction in admission rates. Given the rise in diabetes prevalence, aging population and the need to reduce unnecessary admissions, the appreciation of hypoglycaemia awareness and prevention should be given more attention.

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(16)30091-2/abstract

 

Intensive treatment and severe hypoglycaemia among adults with type 2 diabetes

Rozalina G. McCoyet al. JAMA Internal Medicine. Doi:10.1001/jamainternmed.2016.2275

The UKPDS study demonstrated the benefit of glucose lowering in Type 2 Diabetes (T2DM), a fact reinforced by its legacy study. However, other evidence from ACCORD/ ADVANCE and VADT did raise concerns about intensive glucose lowering especially in patients at higher risk of cardiovascular disease. NICE guidance goes some way in acknowledging this with its messages of individualised glucose targets. This study seems to reinforce the potential problems associated with tight glycaemic control. Looking at >31000 patients who achieved and maintained an HbA1c <7.0% (53mmol/mol), it compared high complexity patients (aged >75years, dementia or end stage renal failure or 3 or more long term conditions) with low intensity patients. Complex patients requiring intensive (aiming for lower than recommended HbA1c targets) had double the frequency of severe hypoglycaemia. The authors calculated that more than 20% of patients with T2DM received unnecessarily intensive treatment. These results further highlight the risk and significance of hypoglycaemia in complex patients which at best is likely to outweigh any perceived benefit of improved control and at worse result in harm to patients.

http://archinte.jamanetwork.com/article.aspx?articleid=2526670

 

https://www.glycosmedia.com/10528-2/

Diabetes and Ramadan practical guidelines

International Diabetes Federation

Ramadan, a holy month for Muslims lasts for 29–30 days, during which time the consumption of food and drink, as well as oral and injected medications, is forbidden between dawn and dusk. This year in the UK, it lasts for 18-20 hours and clearly has a significant impact on patients with all types of diabetes due to marked changes in food and fluid intake which increases the risk of hypoglycaemia, hyperglycaemia and dehydration. Islamic law grants exemption to patients with diabetes but despite this, many still wish to fast. A plethora of guidelines already exist yet the International Diabetes Federation have launched a weighty (146 page) tome which seeks to address all aspects of diabetes management ranging from diet to hypoglycaemic agents. However, despite all the advice, the document is unwieldly and clearly needs distilling for everyday use. Above all, it could be condensed into a single sentence – it is important that the decision to fast is taken on an individual basis taking into account the level of risk involved.

http://www.idf.org/guidelines/diabetes-in-ramadan

 

The changing face of diabetes complications

Edward W Gregg, Naveed Sattar, Mohammed K Ali. The Lancet Diabetes & Endocrinology. D0i: http://dx.doi.org/10.1016/S2213-8587(16)30010-9

The rising incidence of obesity and diabetes is obvious to everyone who is aware of both medical literature and the general media, both of which describe at length the issue of complications arising from the condition. However, the changing trends in complications are not as clear, especially as intervention impacts on glycaemia and other cardiovascular risk factors. This paper reviewed trends in the classic complications of T2DM in high income countries over the last 20 years, demonstrating reductions in myocardial infarction, stroke, amputations and mortality. There is also evidence that the nature of complications may be changing with (in the USA) a reduction in macrovascular disease in the >65s but an increase in the 45-64 year age group. Furthermore, as mortality is reduced, patients are living longer with the condition leading a different spectrum of morbidity, especially renal disease and cancers with the associated financial impact. Although this article is of interest, the authors themselves point out that the data was obtained from high income countries which are not the areas suffering from the most rapid change in diabetes epidemiology. http://www.thelancet.com/journals/landia/article/PIIS2213-8587(16)30010-9/fulltext

 

Glucose tolerance status of Asian Indian women with gestational diabetes at 6 weeks to 1 year postpartum (WINGS-7)

Balaji Bhavadharini et al. Diabetes Research and Clinical Practice. Doi: http://dx.doi.org/10.1016/j.diabres.2016.04.050

Asian women are at high risk of gestational diabetes and are one of the groups of patients to receive universal screening. Furthermore, GDM is a risk factor for T2DM in later life with NICE guidance suggesting testing glycaemic status is reassessed post-partum and then annually in view of the long term risk with fasting glucose or HbA1c the recommended diagnostic tools. This study reviewed the results of 161 post-partum glucose tolerance tests. Whilst only 1.2% of patients were diagnosed with T2DM at 6-12 weeks post-partum, 11.9% developed the condition between 6 weeks-1year with many more showing some evidence of glucose intolerance. Overall, within 1-year post-partum, dysglycaemia occurred in 20.3% of women with a BMI>25 increasing the risk four fold. Interestingly, there were many women who had a normal fasting but abnormal challenge result, a group who would be missed when following NICE guidance. Whilst the study reinforces the significant risk in this group of patients, and the need for strategies to prevent T2DM, their engagement with health care professionals tends to be low.

http://www.diabetesresearchclinicalpractice.com/article/S0168-8227(16)30114-0/abstract

 

Generation of stem cell-derived β-cells from patients with type 1 diabetes

Jeffrey R. Millman et al. Nature. Doi:10.1038/ncomms11463

Islet cell transplantation is available in the UK with seven centres offering this procedure for patients with type 1 diabetes (T1DM). Unfortunately, the immune process that leads to the beta-cell destruction responsible for T1DM has memory and reactivates leading to islet cell loss. This means that long-term independence from insulin is rare without frequent top-ups of islets; the lack of donor pancreata (all from deceased people) means that this is not an option. The authors of this publication previously reported scalable in-vitro production of functional stem cell-derived beta-cells. Here they describe the generation of beta-cells from T1DM patients. These cells express beta-cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice and respond to anti-diabetic drugs. In addition, they were able to investigate how the cells responded to different forms of beta-cell stress. Using these assays, they found no major differences between these T1DM-derived beta-cells versus those from non-diabetic patients. These results open up all sorts of exciting possibilities for the treatment of T1DM.

http://www.nature.com/ncomms/2016/160510/ncomms11463/full/ncomms11463.html

 

The impact of primary care organization on avoidable hospital admissions for diabetes in 23 countries

Tessa Van Loenen et al. Scandinavian Journal of Primary Health Care. Doi:10.3109/02813432.2015.1132883

Modern management of type 2 diabetes typically proposes a model where patients are managed in primary care until the complexity of their disease requires specialist involvement. This will vary according to the levels of education and enthusiasm in primary care but might encompass the stage when insulin initiation is required to instances where secondary care multidisciplinary teams are needed (such as pregnancy, renal management and foot complications). One would assume that countries with ‘strong’ primary care (and, therefore, the most advanced primary care diabetes services) would have lower levels of diabetes-related hospitalisations; this is what this study set out to examine. Twenty-three counties were included in the analysis and the investigators reported (to their surprise) that ‘in countries where patients experience good access, they have a significantly higher chance of being admitted for long-term complications’. Whilst acknowledging the difficulties in this sort of analysis (there will be huge variation within countries, for example), it highlights that outcomes cannot be second-guessed without doing the research to prove their effectiveness.

http://www.tandfonline.com/doi/full/10.3109/02813432.2015.1132883

 

https://www.glycosmedia.com/10428-2/

 

Filling the knowledge gap in diabetes management during Ramadan

Saud Al Sifri and Kashif Rizvi. Diabetes Therapy. Doi: 10.1007/s13300-016-0168-9

Clinicians treating Muslim patients often struggle with achieving satisfactory glycaemic control during Ramadan. Reasons for this include the vary length of fasting from year to year as well as significant changes to diet and lifestyle during this period. Although there are some treatment guidelines, it is unclear what the evidence base was for them, especially as most diabetes guidelines are designed around non-fasting patients. This paper reviewed the evidence base for managing glycaemic control in T2DM during Ramadan, including 10 RCTs and 20 observational studies. The over-arching finding was the significant heterogeneity in these studies including targets, definition of hypoglycaemia and treatments, for example the lack of studies which looked at DPP4 inhibitors and GLP1 analogues – medications which would be expected to be suited to periods of fasting. Studies tended to concentrate on HbA1c, (which covers 2-3 months) as a measure of glycaemic control, rather than fructosamine which covers the preceding 2-3 weeks. Clearly more rigorous and well designed studies with defined safety and clinical end points are required to refine treatment during Ramadan for patients with T2DM.

http://link.springer.com/article/10.1007%2Fs13300-016-0168-9

 

Accelerated fetal growth prior to diagnosis of gestational diabetes mellitus in nulliparous women

Ulla Sovio. Diabetes Care. Doi: http://dx.doi.org/10.2337/dc16-0160

The HAPO study showed an association between fetal weight and blood glucose levels below the diagnostic thresholds for gestational diabetes (GDM). Current NICE guidance for GDM advises a screening glucose tolerance test at 24-28 weeks. Too early and the diagnosis may be missed, too late and the fetus may have already developed complications, specifically macrosomia. As a result, timing of the diagnostic test attempts to minimise these potential problems. Using sequential ultrasound measurements of fetal abdominal circumference (AC), this prospective study showed that at 20 weeks, there was no association between AC and a future diagnosis of GDM whilst at 28 weeks there was an increased risk of increased AC. Maternal obesity had a similar 28-week association whilst a combination of obesity and GDM had a 5x increased risk of AC.  Additive with obesity, there is a period of accelerated fetal growth at 20-28 weeks before GDM was diagnosed, possibly associated with rising glucose levels. Perhaps the timing of the GTT should be individualised in order to make the diagnosis as early as possible rather than the current uniform approach.

http://care.diabetesjournals.org/content/early/2016/03/31/dc16-0160.abstract

 

A multicenter observational study of incretin-based drugs and heart failure

Kristian B. Filion et al. NEJM. Doi: 10.1056/NEJMoa1506115

Following the (probably inappropriate) demise of rosiglitazone in 2010, all new pharmacotherapies for diabetes are subjected to cardiovascular (CV) outcome trials to prove safety. Five placebo-controlled studies have reported; three gliptins, one GLP-1 RA (lixisenatide) and one SGLT2-inhibitor (empagliflozin). All studies showed non-inferiority for their primary CV end-point (indeed, empagliflozin demonstrated superiority), however, the SAVOR-TIMI 53 trial of saxagliptin threw up the unexpected finding of a significant increase in hospitalisation due to heart failure (HF). The FDA performed a detailed examination of this trial along with the EXAMINE study of alogliptin (which showed a trend towards increased HF) and in April 2016 issued a drug safety communication of increased risk of HF for both agents. Note that the TECOS study of sitagiptin was not considered and it showed no signal for HF risk. This NEJM publication analysed ‘real-life’ health care data from almost 1.5 million patients. The rate of hospitalization for HF did not increase with the use of incretin-based drugs as compared with other oral antidiabetic-drug combinations. Results were similar for gliptins and GLP-1 RAs. Perhaps the SAVOR-TIMI result was a fluke after all.

http://www.nejm.org/doi/full/10.1056/NEJMoa1506115

 

 

The impact of insulin therapy and attitudes towards insulin intensification among adults with T2D

Elizabeth Holmes-Truscott, Jessica L. Browne, Jane Speight. Diabetes and Its Complications. Doi: DOI: http://dx.doi.org/10.1016/j.jdiacomp.2016.03.027

The NICE guidelines for management of type 2 diabetes (NG28), published in December 2015, recommend intensification of treatment when the HbA1c rises to 58mmol/mol (7.5%) and this includes initiation of insulin. This recommendation is not new; dating back to 2002, NICE has advocated the same upper limit for HbA1c, with insulin as the final therapeutic tool to achieve this. However, despite this long-standing guidance, studies show that HbA1c at insulin initiation in the UK is typically more than 75mmol/mol (9%).  Moreover, once started on insulin, around half of patients remain above the 58mmol/mol target with no optimisation. This phenomenon, labelled ‘clinical inertia’, is the subject of a great deal of research. This study reports twenty face-to-face interviews with adults using insulin for up to 4 years. Positive and negative experiences of insulin therapy were reported but most were receptive to insulin intensification, despite the reported barriers. Perhaps this indicates that clinicians (rather than patients) or the NHS environment is the main barrier to insulin. Or maybe, the majority of patients and clinicians don’t buy into the NICE target.

http://www.jdcjournal.com/article/S1056-8727(16)30064-2/abstract

 

The burden of NAFLD and its characteristics in a nationwide population with type 2 diabetes

Gabriele Forlani et al. Journal of Diabetes Research. Doi: http://dx.doi.org/10.1155/2016/2931985

For clinicians who were trained in the 1980-90’s, the presence of fatty liver identified by ultrasound was a common but benign finding in patients with poorly controlled type 2 diabetes (T2DM). Over the past ten years, this phenomenon has been promoted to disease status, termed nonalcoholic fatty liver disease (NAFLD). This publication examines the prevalence of NAFLD and its clinical correlates in 94,577 patients, using the ‘fatty liver index’ (FLI) as a proxy for NAFLD. FLI is an algorithm based on BMI, waist circumference, triglycerides and GGT. FLI-NAFLD was present in 59.6% of patients and, compared to the ‘normals’, was associated with impaired renal function, higher albumin excretion, HbA1c and blood pressure and lower HDL cholesterol. So, should we be assessing liver function tests as part of the diabetes annual review? Apparently not, since the ALT was within normal limits in 73.6% of the FLI-NAFLD patients. A bigger question though, is does the identification of the ‘burden of NAFLD in T2DM’ make any difference, since treatments and targets probably remain the same? You can tell when I trained.

http://www.hindawi.com/journals/jdr/2016/2931985/

 

 

 

 

 

https://www.glycosmedia.com/10309-2/

Effects of SGLT2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes

Jason H Y Wu et al. The Lancet Diabetes & Endocrinology. Doi: http://dx.doi.org/10.1016/S2213-8587(16)00052-8

Hypoglycaemic agents by their very name lower glucose but obviously should be safe from a cardiovascular point of view. The most recent class of drugs, the SGLT2 inhibitors, have rapidly gained acceptance within many guidelines due to their impact on glycaemic control, blood pressure and weight as cardiovascular data emerges. The safety data available to date on these agents was examined in this meta-analysis of regulatory submissions and published trials for a number of SGLT2s. Protection against the risk of cardiovascular events and heart failure was demonstrated although this was not the case for non-fatal MI with an adverse impact on stroke. However, the results from this study were dominated by EMPA-REG which looked at Empaglafozin and, whilst this study has been felt to demonstrate a class effect of benefit in patients with T2DM at high CV risk amongst all SGLT2s, further data will emerge over the next few years. There are enough pharmacological differences between the agents to suggest caution about a class effect – after all, one was though to exist between the glitazones.

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(16)00052-8/fulltext

 

A review of glycemic control in older adults with Type 2 Diabetes

Kasia J. Lipska et al. JAMA. Doi:10.1001/jama.2016.0299

Most current guidelines seem to use the mantra that lower is better with targets in recent NICE guidance reinforcing HbA1c <6.5% (or 7% if the patient is on drugs which cause hypoglycaemia). However, there does seem to be evidence of a U shaped curve with regard to mortality and HbA1c especially in patients at risk of cardiovascular disease. Another group of patients at risk of overzealous glucose lowering is the elderly (over 80s) a group that is excluded from many RCTs used to develop guidelines. In this group of patients, there is limited evidence that intensive glycaemic control reduces macrovascular events whilst tight control needs to be maintained for several years before it impacts on microvascular disease. However, it does increase the risk of significant hypoglycemia, and as a result, in this group of patients, a more relaxed target of 7.5-9.0% may be more appropriate to maximize benefit and minimize harm. As well as more individualized care, this may reduce the need for certain therapies including insulin.

http://jama.jamanetwork.com/article.aspx?articleID=2499252

 

Insulin pump use compared with intravenous insulin during labour and delivery: the INSPIRED observational cohort study

Drever et al. Diabetic Medicine. Doi: 10.1111/dme.13106

Insulin pump therapy (CSII) is an increasingly common modality of treatment for patients with Type 1 diabetes (T1DM) due to the flexibility and control that it allows. However, health care professionals based in specialties outside the ‘diabetes community’ are often unaware as to how to manage patients with this technology. One such example is in pregnancy, especially at delivery where tight control is essential to avoid neonatal hypoglycaemia and where it is not uncommon for the pump to be removed in favour of intravenous insulin. The counter-intuitiveness of this is reinforced in this study from Canada which reviewed 161 patients in labour who were allowed to continue their pump compared to those who were transferred to iv insulin. Women in the pump group had significantly better glycaemic control defined by mean and median glucose values as well as spending more time in the target range than those on iv insulin with no difference in hypoglycaemia between the groups. CSII continuation during labour and delivery should become standard practice especially as these patients are usually capable of dealing with glycaemic variability but further training needs to be given to HCPs as to its benefits.

http://onlinelibrary.wiley.com/doi/10.1111/dme.13106/abstract

 

Long-term benefits of intensive glucose control for preventing end-stage kidney disease: ADVANCE-ON

Muh Geot Wong et al. Diabetes Care. Doi: 10.2337/dc15-2322

The ADVANCE Collaborative Group published its findings on intensive blood glucose control and vascular outcomes in type 2 diabetes in 2008. This was one of three studies, ACCORD and the VADT being the other two, which gave a nihilistic view of the impact of tight glycaemia on large vessel complications (such as heart attack and stroke). No reduction in events was seen (indeed ACCORD showed increased all-cause mortality) and HbA1c targets in the General Medical Services contract were relaxed (from <7.0% [53mmol/mol] to <7.5% [58mmol/mol]). In contrast to the UKPDS, where longer observation showed benefit, ADVANCE-ON (the six-year post-trial follow-up) showed no legacy effect of tight glycaemia on macrovascular events. However, there was a reduction in microvascular events in the original study, primarily driven by a 21% relative reduction in nephropathy (mainly microalbuminuria), providing a continued rationale for tighter HbA1c targets. Now ADVANCE-ON translates these data into the hard endpoint of end-stage kidney disease. The significant reduction of 54% (P<0.01) sounds convincing but actual figures of 29 versus 53 events less so (given the 8,494 patients in follow-up). Perhaps it’s time for more relaxation of targets?

http://care.diabetesjournals.org/content/early/2016/03/19/dc15-2322.abstract

 

Comparative cardiovascular safety of glucagon-like peptide-1 receptor agonists versus other antidiabetic drugs in routine care: a cohort study

Elisabetta Patorno et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12665

Following on from the rosiglitazone controversy, diabetes medications are subjected to cardiovascular outcomes trials (CVOTs) to demonstrate CV safety. Until publication of the EMPA-REG study (which showed CV and all-cause mortality superiority for empagliflozin) the sequence of events was as follows: a meta-analysis of phase 3 trial data would show a signal for CV benefit (usually non-significant due to small event numbers) and then the definitive CVOT would report no difference between drug and placebo. This applied to saxa-, alo- and sitagliptin as well as lixisenatide. This study reverses that sequence. Within a large U.S. health database, the authors identified three cohorts of metformin-treated T2DM patients who initiated GLP-1 RA versus: a DPP-4i (N=35,534); 2nd generation sulfonylureas (N=28,138); or insulin (N=47,068), between 2005 and 2013. In this real-world study, they found no significant differences between drug initiation and a composite CV endpoint of hospitalisation for acute myocardial infarction, unstable angina, stroke, or coronary revascularization. Coincident and in contrast to this came a press release from Novo Nordisk reporting superiority of liraglutide from the LEADER CVOT – the final results will appear in June.

http://onlinelibrary.wiley.com/doi/10.1111/dom.12665/abstract

 

https://www.glycosmedia.com/10220-2/

National survey of the management of Diabetic Ketoacidosis (DKA) in the UK in 201

K. Dhatariya et al. Diabetic Medicine. Doi: 10.1111/dme.12875

Diabetic ketoacidosis (DKA) is a medical emergency requiring hospital admission and treatment which essentially consists of fluid, insulin and electrolyte replacement as indicated by a plethora of local and national guidance. The causes of DKA are also usually clear including intercurrent illness and insulin omission. In view of this, results from the 2014 national survey of DKA treatment does raise concerns. The survey from all specialist teams on 5 consecutive patients shows significant variability of care, varying from length of time before treatment was initiated to the time until the DKA had resolved. Of concern was the number of patients developing DKA whilst in hospital (7.8%) and the number of complications encountered during treatment including hypoglycaemia (27.6%) and hypokalaemia (55%). Although most patients were not seen by members of the diabetes specialist team within 6 hours of admission, 95% were seen before discharge. Overall, it is one thing to develop nationally accepted guidelines but another to implement them without which length of stay and risk to patients can be increased. Rolling education programs for junior doctors and nurses would be one way to address this.

http://onlinelibrary.wiley.com/doi/10.1111/dme.12875/abstract

 

Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes

Ling Li et al. BMJ. Doi: http://dx.doi.org/10.1136/bmj.i610

DPP-4 inhibitors (gliptins) have gained rapid acceptance into guidelines for treating hyperglycaemia as a second line agent. Their advantages are obvious, lowering HbA1c without the negatives of weight gain or hypoglycaemia. However, as the companies produce their CV safety studies, concerns have been raised regarding a possible link to heart failure. In particular, the SAVOR-TIMI study suggested an increased admission rate for patients on Saxagliptin with heart failure although this was not shown in both the EXAMINE (Alogliptin) and TECOS (Sitagliptin) studies. The issue of heart failure was examined in more detail in this systematic review of 55 studies. Whilst the review acknowledged the variability of many of these studies, including the fact that the majority were pharmaceutically funded and that there is a bias to the larger studies listed above, both randomised controlled trials and observational studies suggest that these drugs may increase the risk of hospital admission for heart failure. These patients tended to have pre-existing cardiovascular disease or multiple risk factors for it. Whilst neither the FDA or EMA have recommended that the drugs are prescribed according to license, the potential risk is worth bearing in mind as treatment is individualised.

http://www.bmj.com/content/352/bmj.i610

 

Pioglitazone after ischemic stroke or transient ischemic attack

Walter N. Kernan et al. NEJM. Doi: 10.1056/NEJMoa1506930

The place of pioglitazone in the management of type 2 diabetes remains uncertain. New initiations have reduced for several reasons. First, there was collateral damage caused by the withdrawal of rosiglitazone due to controversy regarding an increased risk of myocardial infection. This occurred despite there being positive cardiovascular (CV) data for pioglitazone (from the PROACTIVE study) and has not reversed by the FDA changing its mind and giving rosiglitazone a clean bill of CV health. Then there are the class-specific adverse effects of glitazones; weight gain, partly due to fluid retention which can lead to congestive cardiac failure and increased risk of bony fractures. Finally, there was a scare concerning bladder cancer, leading to withdrawal of piogitazone in France but which now seems to have dissipated following long-term prospective follow-up of the Kaiser-Permanente insurance data-base.

This study showed that in a non-diabetic population affected by cerebrovascular disease, pioglitazone reduced the risk of vascular outcomes, consistent with insulin resistance an underlying risk factor (the original selling point of glitazones). Interesting data but I suspect the damage has been done and this study will have little impact on prescribing.

http://www.nejm.org/doi/full/10.1056/NEJMoa1506930

 

9-Year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes

Hertzel C. Gerstein. Diabetes Care. Doi: 10.2337/dc15-2283

The ACCORD study was published in 2008 and had a major impact on how we manage patients with type 2 diabetes (T2DM). Prior to ACCORD, glycaemic targets were tighter in patients with evidence of large vessel complications. All this changed when ACCORD was ended prematurely, having found an increase in cardiovascular and all-cause mortality. Along with two other studies, showing no CV benefit from tighter glucose control, it created a nihilistic view of glucose management (to the delight of cardiologists) and led to relaxation of the HbA1c target in the GMS contract from 7.0% to 7.5% (53 to 58mmol/mol). Long-term follow-up of the UKPDS, suggesting a CV benefit of tight control from diagnosis of T2DM, somewhat tempered this view but large vessel disease is now a reason for relaxing rather than tightening glucose targets. ACCORDIAN is the 4-year follow-up of 8,601 (98%) of the original ACCORD cohort and reports that a mean of 3.7 years intensive glycemic control had a neutral effect on death and nonfatal cardiovascular events but increased cardiovascular-related death. So, a bit less negative, but still bad news and no reason to change current practice.

http://care.diabetesjournals.org/content/early/2016/01/20/dc15-2283.abstract

 

Statins for people with type 1 diabetes: when should treatment start?

Miles Fisher. Practical Diabetes. Vol. 33 No. 1

This review highlights the paucity of data concerning lipid lowering in type 1 diabetes (T1DM), contrasting the massive evidence base showing the benefit in T2DM. It criticises guidelines from 2014 recommending expansion of the number of T1DM patients for whom statins may be prescribed. These are NICE clinical guideline 181, suggesting all adults with T1DM should be considered for statins and Joint British Societies’ consensus recommendations (JBS3) implying that all patients aged over 30 years be treated. The use of atorvastatin 20mg is also contested on the basis that simvastatin was used in the trials. Whilst technically correct, I feel the article is over-zealous. Benefits of statins in T1DM recruits in trials are of similar magnitude to those in T2DM, albeit non-significant due to smaller numbers. Most would accept that CV benefits of statins are a class-effect, so why not use a potent one? And, if (as is proposed) all patients aged 40 years are treated, why not intervene in the progressive atherosclerotic process earlier? If I was a T1DM patient, I think I would like to have that as an option.

http://www.practicaldiabetes.com/SpringboardWebApp/userfiles/espdi/file/January%202016/Ldr%20Fisher%20laserwords.pdf

 

https://www.glycosmedia.com/10125-2/

Sulfonylurea use and the risk of hospital readmission in patients with type 2 diabetes

Pamela C. Heaton et al. BMC Endocrine Disorders. Doi: 10.1186/s12902-016-0084-z

Sulphonylureas (SUs)have been a mainstay of glycaemic control for many years and as a result, reinforced by multiple iterations of guidelines which placed them early in the treatment pathway, clinicians are comfortable with using them. However, their well-documented side effects, specifically hypoglycaemia are increasingly recognized as problematic. Furthermore, hypoglycaemia is a common cause for hospital admission especially in the elderly, with some patients being admitted on multiple occasions. This US study compared the risk for diabetes–related hospital readmission in patients with type 2 diabetes treated with sulphonylureas compared to those treated with other oral hypoglycaemic agents (OHAs). In this readmission cohort, 23.2% were taking SUs whilst 16.1% of readmitted patients were taking other OHAs – a 30% increase. Although other OHAs such as gliptins and SGLT2 inhibitors are relatively expensive compared to SUs, this cost may be offset if only a handful of admissions are prevented. Indeed, the risk of hypoglycaemia is now mentioned in the recent NICE guidance on hypoglycaemic agents in Type 2 Diabetes.

http://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-016-0084-z

 

Effect of diabetes and glycemic control on ischemic stroke risk in AF patients

Jeffrey M. Ashburne et al. Journal of the American College of Cardiology. Doi: 10.1016/j.jacc.2015.10.080

Atrial fibrillation is a well recognised risk factor for ischaemic stroke, a risk that is increased in patients with diabetes. Duration of diabetes is also a documented risk for stroke, risk increasing by 3% per year and tripling after 10 years. This study examined both of these risks by examining the association between duration of diabetes and elevated HbA1c and ischaemic stroke in a US community based cohort of AF patients. Duration of diabetes was divided into <3 years or >3 years whilst an HbA1c of 9% and 7-9% were the glycaemic control groups. Neither glycaemic control groups were found to be associated with an increased risk of stroke. However, duration of diabetes >3 year was associated with an increased risk (hazard ration 1.74), this relationship being independent of the patients age. Potential mechanisms for this include the enhanced thrombin generation and impaired fibrinolysis which occur in diabetes. This study reinforces the benefit of using duration of diabetes rather than just the diagnosis when calculating risk – an example being the UKPDS risk engine which uses both duration of diabetes and the presence of atrial fibrillation in its algorithms.

http://content.onlinejacc.org/article.aspx?articleID=2481278

 

The UK NSC recommendation on Diabetic Retinopathy screening in adults

UK National Screening Council

Annual retinal screening has been a cornerstone of diabetes care in the UK for over a decade and is now part of the 9 NICE diabetes care standards. However, the epidemiology of diabetes is increasingly putting screening programs under pressure as they struggle with creating the capacity to screen ever rising numbers of patients within the required period. Until recently, retinal screening guidance has been a ‘one size fits all’ process which is not in keeping with individualised care now recommended by NICE. As a result, many patients at low risk of developing sight threatening retinopathy (defined as patients having two successive clear eye screening appointments) have regular screening sessions making it harder to find appointments for those for whom more regular and targeted screening is required. Following an observational study following > 350000 patients for four years which looked at progression of retinopathy in seven screening programs, the UK National Screening Council has changed its guidance in January 2016 to recalling low risk patients every 2 years. However, it continues to recommend that annual screening should remain for those at higher risk of sight loss.

http://legacy.screening.nhs.uk/diabeticretinopathy

 

Glucose test provenance recording in UK primary care: was that fasted or random

P. McGovern et al. Diabetic Medicine. Doi: 10.1111/dme.13067

The authors report the effect of provenance recording on the interpretation of glucose tests requested in primary care. ‘Provenance’ indicates that the nature of the test (e.g. fasting, oral glucose tolerance test, random, none specified) has been documented with its result and the presumption is that absence of provenance indicates failure by the requesting clinician, rather than laboratory omission. A cross-sectional analysis was conducted of glucose measurements from the Royal College of General Practitioner Research and Surveillance Centre database, which includes primary care records from more than 100 practices across England and Wales. All glucose results recorded during 2013 were identified. Over two million people were included in the cross-sectional analysis. Of 203 350 recorded glucose measurements the majority (117 893; 58%) did not have any provenance information. Analysis of data from a single practice showed that this caused unnecessary repeated testing, delayed diagnosis and wasted clinician time. This lends support to the current recommendation that diagnosis of type 2 diabetes should be made by testing HbA1c, where provenance is immaterial.

http://onlinelibrary.wiley.com/doi/10.1111/dme.13067/abstract

 

The renal threshold for glucose re-absorption predicts diabetes improvement by sodium glucose co-transporter 2 inhibitor therapy

Aya Osaki et al. Journal of Diabetes Investigation

There are currently eight classes of glucose-lowering medicines in the UK and various guidelines as to how to combine them. Guidelines generally advocate individualisation of therapy using patient characteristics (e.g. weight, hypoglycaemia risk) but not according to whether a subject is likely to respond to an individual treatment. This is because for the newer classes, such as gliptins and GLP-1RA injectables, it has not been possible to identify clinical features of ‘responders’ versus ‘non-responders’. Hence therapy is based on ‘suck it and see’. To this point, the same applied to the sodium-glucose co-transport 2 inhibitor (SGLT2i) class, however, this publication might change that. The authors assessed the renal threshold for glucose re-absorption using a simple spot urine test and then examined the patient response to ipragliflozin (an SGLT2i not available in the UK). They revealed a negative correlation between HbA1c improvement and the renal glucose threshold, suggesting that this test will identify responders to SGLT2i treatment. Simple means of targeting therapy to those who will respond is potentially time and money-saving. Confirmatory data from a UK population are needed.

http://onlinelibrary.wiley.com/doi/10.1111/jdi.12473/abstract

https://www.glycosmedia.com/10001-2/

Gestational diabetes mellitus in early pregnancy: evidence for poor pregnancy outcomes despite treatment

Arianne N. Sweeting et al. Diabetes Care. Doi: 10.2337/dc15-0433

The recognition that women with diabetes have adverse pregnancy outcomes has been known for many years – indeed, addressing this was one of the pillars of the 1989 St Vincent declaration. As a result, over the last few years, reinforced in the 2015 NICE guidance, increasing attention has been given to managing women with dysglycaemia in pregnancy – both those with pre-existing diabetes and identifying those with gestational diabetes (GDM). This US study examined pregnancy outcomes in women with pre-existing T2DM and those identified with GDM at <12 (early), 12-23 and >24 weeks. Adverse outcomes including pre-eclampsia, pre-term delivery and neonatal jaundice were more prevalent in women with pre-existing T2DM and early (<12 weeks) GDM than those identified with GDM later in pregnancy. There was no difference in outcomes between early GDM and T2DM indicating the need to proactively treat hyperglycaemia in early pregnancy. However, experience suggests that significant numbers of patients with ‘early GDM’ actually have pre-existing T2DM which reinforces the need to confirm a women’s glycaemic status post partum.

http://care.diabetesjournals.org/content/early/2015/12/07/dc15-0433.abstract

 

Diabetes medications with cardiovascular protection in the wake of EMPA-REG OUTCOME

Robert EJ Ryder and Ralph A Defronzo. British Journal of Diabetes. Doi: http://dx.doi.org/10.15277/bjdvd.2015.045

Reducing the elevated risk of cardiovascular disease in T2DM is the main aim of patient treatment. Whilst certain treatments are well established, specifically statins and anti-hypertensive’s, the benefit of hypoglycaemic agents is more controversial. The benefits of Metformin were clearly established in the UKPDS study where a reduction in cardiovascular death was demonstrated in patients with early T2DM – although this did not become apparent for several years.  The PROACTIVE study demonstrated the benefit of Pioglitazone in reducing CV death, myocardial infarction and stroke. It also reduces carotid intimal thickness, suggesting a slowing down of the atherosclerotic process. More recently, the EMPA-REG study demonstrated a reduction in CV death in high risk patients – but not non-fatal MI or stroke, signifying a different mechanism to that of Pioglitazone. Furthermore, the diuretic effect of Empagliflozin may mitigate the fluid retention of Pioglitazone. As a result, a combination of Metformin, Pioglitazone and Empagliflozin may be an effective combination of agents for patients with T2DM at high CV risk. However, given that both Metformin and Pioglitazone are off patent, it is unlikely that this combination will be tested by clinical trial.

http://bjdvd.co.uk/index.php/bjd/article/view/103/221

 

Standards of medical care in diabetes

American Diabetes Association. January 2016; 39 (Supplement 1)

For the whole of 2015, healthcare professionals in the UK observed the agonies of the National Institute for Health and Care Excellence (NICE) as it struggled to produce new guidelines for the management of type 2 diabetes. This was an update of the NICE clinical guideline published in 2008 (with a glycaemic therapy revision in 2009). Contrast this with the situation in the United States, where the American Diabetes Association (ADA) produces an annual update of its ‘Standards of Medical Care in Diabetes’, a comprehensive suite of documents dealing with all aspects of the condition. Back in 2009, there was a much greater consensus between UK and US practice, with similar targets for HbA1c, blood pressure, lipids and aspirin use. Today, significant divergence is beginning to emerge. In the US, HbA1c targets are less prescriptive, whilst options for pharmacotherapy are much more flexible. Lipid management remains focused on LDL-cholesterol, whereas in the UK non-HDL-cholesterol has become the focus. Use of aspirin is also encouraged, whereas NICE now precludes its use for primary prevention. Same evidence, different recommendations….

http://care.diabetesjournals.org/site/misc/2016-Standards-of-Care.pdf

 

Mean HbA1c and mortality in diabetic individuals with heart failure: a population cohort study

Douglas H.J. Elde et al. European Journal of Heart Failure. Doi: 10.1002/ejhf.455

Interest in heart failure (HF) and type 2 diabetes (T2DM) was rekindled in 2013 following the publication of two cardiovascular (CV) safety trials of DPP-4 inhibitors. The SAVOR-TIMI 53 study reported a significant increase in hospitalisation for HF with saxagliptin (3.5% vs. 2.8% placebo; P=0.007). The EXAMINE study, compared alogliptin with placebo and whilst there was no significant increase in HF, a trend was observed. These results had several impacts. Cardiologists argued that HF should be included as a CV outcome (previously composites of myocardial infarction, stroke +/- angina had been used) and some clinicians no longer prescribed DDP4is. There was also a hypothesis that all glucose-lowering strategies might increase HF risk, as glucose might be the major energy substrate for the failing heart. Reassurance came when the TECOS trial of sitagliptin showed no increase in HF and this publication from Scotland supports that concept that tight glycaemic control in itself is not a risk. However, a U-shaped mortality curve was seen for time-weighted mean HbA1c suggesting that certain therapies (insulin and sulphonylureas) may be harmful; the jury is still out.

http://onlinelibrary.wiley.com/doi/10.1002/ejhf.455/abstract

 

 Association between use of warfarin with common sulfonylureas and serious hypoglycemic events

John A Romley et al. BMJ. Doi: http://dx.doi.org/10.1136/bmj.h6223

Debate around the safety of the sulphonylurea (SU) class of antidiabetic agents continues to rage. Whilst no-one doubts the association with hypoglycaemia and weight gain, the question of whether these side-effects (and/or others) lead to an increase in cardiovascular (CV) mortality is unresolved. This is despite reassuring results from the United Kingdom Prospective Diabetes Study (UKPDS) in 1998, a trial which was specifically designed to address this issue. So, over the last few years, there have been several meta-analyses suggesting increased CV risk, and SUs have slowly moved down the treatment algorithm for type 2 diabetes (including the most recent guideline from NICE). This retrospective cohort analysis from the US of 465,918 patients prescribed SUs reports that those receiving warfarin medication were more likely to attend secondary care due to hypoglycaemia, consistent with an adverse drug interaction. Whilst this type of analysis cannot attribute cause-and-effect (for example, being on warfarin might imply worse renal function, hence increased hypoglycaemia risk), it does suggest that co-prescribing with SUs should be avoided. More ammunition for the anti-SU lobby.

http://www.bmj.com/content/351/bmj.h6223

 

 

 

https://www.glycosmedia.com/9895-2/

 Type 2 diabetes in migrant south Asians: mechanisms, mitigation, and management

Naveed Sattar and Dr Jason M R Gill. The Lancet Diabetes & Endocrinology. Doi: http://dx.doi.org/10.1016/S2213-8587(15)00326-5

Managing diabetes in S. Asian patients present unique challenges including attention to diet and other lifestyle issues. Despite education about diabetes prevention, S. Asians are at significantly elevated risk of T2DM compared with white Europeans and usually develop the condition up to 10 years earlier and at a lower BMI. Reasons for this include increased insulin resistance in this population and potentially β cell failure at an earlier age. Although there are no clear genetic factors predisposing this, Asian patients have different levels of adiposity (high percentage of body fat and high proportion of deep subcutaneous and visceral fat) and skeletal muscle (low percentage of lean mass and low cardio respiratory fitness). These findings need to be reflected in a more targeted approach to treatment e.g. recognition of different BMI values and the subsequent need to address weight and physical fitness. Over time, CV risk has been attenuated, possibly with more proactive use of statins, and hypertensive’s etc., but, due to problematic and persistent hyperglycaemia (HbA1c in S Asians tends to be higher than in Europeans) retinopathy and renal complications remain a major problem and requires further attention.

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00326-5/abstract

 

Pregnancy and neonatal outcomes in gestational diabetes treated with regular insulin or fast-acting insulin analogues

You J.Y et al. Gynecologic and Obstetric Investigation. Doi:10.1159/000440616

The 2015 NICE guidelines recommend fast acting insulin analogues (aspart and lispro) over human insulin. Much of the evidence for this comes from patients with Type 2 diabetes who become pregnant rather than those who present with gestational diabetes (GDM). This study investigated 197 women with GDM requiring insulin and randomised them into receiving a fast acting analogue or regular human insulin. The study revealed no significant difference between the groups for a variety of maternal and foetal outcomes including macrosomia, emergency caesarean section and neonatal hypoglycaemia. Although the data from this study revealed similar outcomes between analogue and regular insulin, the former will still be used first line in all diabetic pregnancies because of their established advantages including time of administration and maternal hypoglycaemia. They are also more effective at addressing the 1-hour post meal glucose target, recommended by NICE.

http://www.karger.com/Article/Abstract/440616

 

Clinically significant chronic liver disease in people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study

Joanne R. Morling et al. QJM. Doi: http://dx.doi.org/10.1093/qjmed/hcv191

Liver disease is a common finding in Type 2 diabetes (T2DM) and presents as a spectrum of disorders ranging from fatty liver (Non-alcoholic fatty liver disease) through to frank cirrhosis and hepatocellular carcinoma via Non-alcoholic steatohepatitis (NASH). Despite this, however, the association of liver disease and diabetes is not always appreciated by health care professionals Furthermore, the exact disease burden is unknown with patients often being found incidentally through liver function testing. This study was performed to examine the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease. Patients enrolled in the Edinburgh T2DM study underwent liver ultrasound and other liver tests. The study revealed a liver disease prevalence of 2.2% with patients having a higher incidence of systemic inflammation and hepatic fibrosis markers. The study confirmed the association of T2DM with a raised incidence of liver disease. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Lifestyle changes will need to be reinforced in patients identified with liver disease given the relative paucity of therapeutic interventions.

http://qjmed.oxfordjournals.org/content/early/2015/10/09/qjmed.hcv191

 

LDL cholesterol is not a good marker of cardiovascular risk in Type 1 diabetes

Hero et al. Diabetic Medicine. Doi: 10.1111/dme.13007

People with type 1 diabetes (T1DM) frequently resent being lumped together with those who have the type 2 (T2DM) version. Children report being accused of bringing the condition upon themselves whilst adults are denied adequate access to testing strips, both on the basis that they have T2DM. This publication suggests that extrapolation of lipid targets from T2DM to T1DM may also be inappropriate. The authors followed a cohort of 30,778 patients with T1DM from 2003-06 until 2011 and examined the predictive value of LDL-cholesterol (LDL-C) and total/HDL-cholesterol (HDL-C) ratio for cardiovascular disease (CVD). They report that LDL-C is not a good predictor of CVD in this group and suggest that LDL-C targets should be revisited. Perhaps this shouldn’t be a surprise. It is well documented that patients with T1DM who do not develop nephropathy and, by virtue of this, are at low risk of CVD have elevated HDL-C levels. Indeed, they have a phenotype which is the exact opposite of that seen in T2DM; insulin sensitivity, normotension and low body weight. Why would anyone treat them in the same way?

http://onlinelibrary.wiley.com/doi/10.1111/dme.13007/abstract

 

Gastrointestinal actions of GLP-1 based therapies: glycaemic control beyond the pancreas

Mark M. Smits et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12593

Glucagon‐like peptide‐1 (GLP‐1) lowers postprandial glucose levels by regulating pancreatic islet‐cell function, with stimulation of insulin (beta-cells) and suppression of glucagon secretion (alpha-cells). In addition, gastrointestinal (GI) actions of GLP‐1 may be as important for glucose‐lowering; GLP‐1 slows gastric emptying and small bowel motility, delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, GLP‐1 may stimulate hepatic glucose uptake, and suppresses hepatic glucose production. This article focusses on GLP‐1 receptor agonists (RAs), the class of anti-diabetic injectables which mimic the effects of GLP‐1 and highlights that individual agents have different impacts on pancreatic versus GI function. This provides a rationale for why GLP-RAs are still effective in long-standing diabetes with so-called ‘beta-cell exhaustion’. It also points to differences between human and small animal physiology, which has guided much of the drug development in this area (the effects in animal models are almost entirely islet-cell mediated). The article misses the opportunity to mention other GLP-1 effects – receptors are also located in the brain, heart and kidney – and the potential for their use in other conditions, Parkinson’s disease being an area of active research.

http://onlinelibrary.wiley.com/doi/10.1111/dom.12593/abstract

 

 

 

https://www.glycosmedia.com/9788-2/

Bariatric–metabolic surgery versus conventional medical treatment in obese type 2 diabetes

Geltrude Mingrone et al. Lancet. Doi: http://dx.doi.org/10.1016/S0140-6736(15)00075-6

After rewriting its draft guidance on Type 2 diabetes, NICE still do not incorporate bariatric surgery in their treatment algorithm despite a plethora of evidence suggesting that it is more effective than medical treatment. However, a caveat may be because many studies are short term with regards to diabetes remission. This study to assess 5 year outcomes of medical versus surgical treatment was designed to look at outcomes up to and beyond 5 years in a total of 60 patients. It is worth mentioning that the surgical procedures were either Roux-en-Y gastric bypass or bilipancreatic diversion, the latter not being a common procedure in the UK. More of the surgical patients reached HbA1c levels of <6.5%. This group also demonstrated more significant improvement in their lipid profiles and blood pressure. In those patients who went into remission from diabetes, after 5 years, 53% of the bypass and 37% of the biliopancreatic diversion patients relapsed. So, despite significant weight loss and early remission from diabetes, the glycaemic control of these patients should still be monitored because of the potential to relapse.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00075-6/abstract

 

 

Earlier intensified insulin treatment of T1D – association with long-term macrovascular & renal complications

Rathsman et al. Diabetic Medicine. DOI: 10.1111/dme.12897

As with the UKPDS and DCCT legacy studies, this study re-examined patients originally enrolled into the Stockholm Diabetes study.  Patients originally recruited in 1982-84 were prospectively re-evaluated until 2011 with regard to all cause mortality and composite mortality including MI, stroke and end stage renal failure. Despite 28 years of follow up, there was no difference in the incidence of macro vascular disease or end stage renal disease between the previously intensive and conventionally treated groups. These groups had shown differences in HbA1c which disappeared after the original study. This study contrasts significantly with the DCCT (Type 1) and UKPDS (Type 2) which reinforced the concept of metabolic memory where early intervention lead to sustained long term effects although this study looked at a mere 102 patients.

http://onlinelibrary.wiley.com/doi/10.1111/dme.12897/abstract

 

Association between hyperglycaemia and adverse perinatal outcomes in south Asian and white British women

Dr Diane Farrar et al. The Lancet Diabetes & Endocrinology. Doi: http://dx.doi.org/10.1016/S2213-8587(15)00255-7

 

Gestational diabetes (GDM) has a significant impact on babies including them being large for gestational age (LGA) and having a future risk of obesity. This has been recognised in the 2015 NICE guidance which has changed the threshold for diagnosis. However, it is well recognised that S Asian women have a higher risk of GDM, complicated by the fact that their babies tend to have a lower risk of LGA but have increased adiposity. The Born in Bradford study has collected a significant amount of information from a large cohort of women including large numbers of S Asian origin and assessed the association between maternal glucose and adverse perinatal outcomes to assess whether the threshold to diagnose GDM should vary depending on ethnicity. A fasting glucose concentration of 5·4 mmol/L or a 2 h post-load level of 7·5 mmol/L identified white British women with 75% or higher relative risk of LGA or high infant adiposity; in south Asian women, the cutoffs were 5·2 mmol/L or 7·2 mmol/L. The data suggests that current NICE guidelines may be diagnosing too few S Asian women with GDM and that lower thresholds should apply to this group. This is in keeping with IADSP and WHO guidance for GDM but would have a major impact on already stretched diabetes services if it was introduced.

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00255-7/abstract

 

 Use of an α-Glucosidase Inhibitor and the Risk of Colorectal Cancer in Patients with Diabetes

Yao-Hsien Tseng et al. Diabetes Care. Doi: 10.2337/dc15-0563

 

It has previously been suggested that there may be an association between diabetes therapies and malignancy. Inhaled insulin was reported to increase the incidence of lung cancer and this was followed by concerns regarding the incretin therapies (pancreatic cancer) and bladder cancer, with both pioglitazone and dapagliflozin. Fortunately, none of these have been confirmed, nevertheless examination of cancer risk for diabetes therapies has become a legitimate activity. This publication from Japan examines the risk of colorectal cancer in patients being treated with acarbose. Less than 2% of acarbose is systemically absorbed and so the potential for alteration in malignancy risk is limited to the bowel. They conducted a nationwide, population-based study using the Taiwan National Health Insurance Research Database. Over one million patients with newly diagnosed diabetes were enrolled between 1998 and 2010. There were 1,332 incident cases of colorectal cancer with a rate was 89.6 cases per 100,000 person-years. Patients treated with acarbose had a 27% reduction in risk with a dose-dependent manner. Unfortunately, the bowel-related side-effects of acarbose mean that few patients in the UK will benefit…

http://care.diabetesjournals.org/content/early/2015/08/21/dc15-0563.abstract

 

Statins and the Risk of Pancreatic Cancer in Type 2 Diabetic Patients – A Population-Based Cohort Study

Mei-Jyh Chen et al. International Journal of Cancer. Doi: 10.1002/ijc.29813

 

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States; only 4% of patients survive 5 years due to late diagnosis. Type 2 diabetes (T2DM) is a risk factor for pancreatic cancer with duration of T2DM greater than 5 years associated with a 50% increased relative risk. Several studies have suggested that statins possess anti-cancer potential through inhibition of cell cycle proliferation, induction of apoptosis and suppression of tumor progression. This study was another retrospective population-based cohort study using the National Health Insurance Research database (NHIRD) in Taiwan. This time patients diagnosed with a first-time diagnosis of T2DM between 1997–2010 were examined and the event of interest was newly diagnosed pancreatic cancer. In the 450,282 patients defined as ‘statin users’ 0.14% developed pancreatic cancer whereas in the 690,335 patients labelled as ‘statin nonusers’ this event occurred in 0.25%. Statin use significantly decreased the risk of pancreatic cancer with a significant dose-effect – the higher the exposure to statin, the lower the risk.

http://onlinelibrary.wiley.com/doi/10.1002/ijc.29813/abstract

 

 

https://www.glycosmedia.com/9585-2/

The primary glucose-lowering effect of metformin resides in the gut, not the circulation

John B. Buse et al.  Diabetes Care.  Doi: 10.2337/dc15-0488

Until the publication of UKPDS results in 1998, there had been scepticism of how effective a treatment metformin (MF) was for glucose-lowering in type 2 diabetes (T2DM). Some even suggested its main effect was to enhance dietary compliance by inducing nausea. Today, we regard metformin as a ‘wonderdrug’, first in all diabetes guidelines and cheap to boot, but we still don’t really understand how it works. Intriguingly, there has previously been a small study showing that intravenous metformin had no impact on hepatic glucose production or peripheral glucose utilisation. These studies lend more weight to the hypothesis that the primary effect of MF is in the bowel. The authors first demonstrated that, dose-for-dose, the bioavailability of delayed-release MF (MFDR) was around 50% that of the standard and extended release MF preparations. They then showed a 40% higher potency in glucose-lowering of MFDR after 12 weeks administration in T2DM. MFDR has been formulated to deliver drug to the lower bowel with lower plasma exposure. At the same time, it is producing a better glycaemic response, consistent with a bowel-mediated mechanism of action for MF.

http://care.diabetesjournals.org/content/early/2015/08/07/dc15-0488.abstract

 

Insulin administered by needle-free jet injection corrects marked hyperglycaemia faster in overweight or obese patients with diabetes

Helena M. de Wit et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12550

Insulin administration by jet injection is a needle-free alternative to conventional injections, which delivers insulin at high velocity (typically >100m/s) across the skin, dispensing it over a larger subcutaneous area than insulin injected with a needle. This method of insulin administration, first developed in the 1950s, is available in the UK and may be considered for needle phobic diabetic patients or any patient that would like the choice to take insulin without a needle. The device known as the InsujetTM, which was also assessed in this study, is bigger than the typical ‘insulin pen’ and it is more complex to use. Users, however, report less discomfort and the larger distribution of insulin in the subcutaneous tissue, leads to a more rapid onset of action. The authors hypothesised that jet injections would lead to a more rapid resolution of marked hyperglycaemia (18-23mmol/L) than subcutaneous administration of rapid-acting insulin analogue (aspart) and this was confirmed. Whether this is clinically relevant is doubtful and it will be interesting to see how it compares with the new ultra-fast acting insulin analogue currently in development.

http://onlinelibrary.wiley.com/doi/10.1111/dom.12550/abstract

 

Risk of atrial fibrillation in diabetes mellitus: A nationwide cohort study

Jannik L Pallisgaard et al. Preventative Cardiology. Doi: 10.1177/2047487315599892

The aim was to investigate the risk of atrial fibrillation (AF) in patients with diabetes in Denmark. Through nationwide registries the authors included people 18 years of age and without prior AF from 1996 to 2012. The cohort included 5,081,087 persons, 4,827,713 (95%) in the background population and 253,374 (5%) in the diabetes group. Incidence rates of AF per 1000 person years were stratified in four age groups: 18 to 39, 40 to 64, 65 to 74 and 75 to 100 years. Adjusted incidence rate ratios in the diabetes group were 2.34 (confidence intervals; 1.52–3.60), 1.52 (1.47–1.56), 1.20 (1.18–1.23) and 0.99 (0.97–1.01) in the four age groups, leading to the headline regarding screening. Whilst screening for AF is becoming feasible with mobile devices, there is an alternative interpretation of these data. First, in the very elderly diabetes cohort, the risk of AF was no different to that of the background population. Second, the youngest diabetes cohort had a lower incidence of AF than the background population aged over 40 years. Is screening justified? – I don’t think so.

http://cpr.sagepub.com/content/early/2015/08/07/2047487315599892.abstract

 

Hypoglycaemia in adults with insulin-treated diabetes in the UK: self-reported frequency and effects

M. Frier, M. M. Jensen and B. D. Chubb. Diabetic Medicine. Doi: 10.1111/dme.12878

Two major issues that affect insulin treated patients are weight gain and hypoglycaemia. With regard to the latter, many patients will do anything to avoid it, even if this means sacrificing tight glycaemic control. Whilst health care professionals usually focus on severe hypoglycaemia requiring third party assistance, non-severe hypoglycaemia which can be self treated by the patient can still be debilitating and have a significant impact on a patient’s quality of life. This UK based study quantified the self-reported frequency of non-severe hypoglycaemia and its effects in adults with insulin-treated diabetes. More than 1000 adults with insulin treated diabetes (Type 1 and Type 2) reported the frequency of hypoglycaemia. Type 1 patients had a mean of 2.4 episodes whilst Type 2 had a mean of 0.8 episodes per week. The consequences of these hypos including fatigue and poor concentration was significant especially with nocturnal hypos. Hypoglycaemia was followed by a period of looser control in most patients. The effect on employment was also significant with time lost. Of interest, most of these episodes were not reported to their health care professional reinforcing the under recognition that these episodes have on quality of life and overall control.

http://onlinelibrary.wiley.com/doi/10.1111/dme.12878/abstract

 

Fasting until noon triggers increased postprandial hyperglycemia and impaired insulin response after lunch and dinner in individuals with type 2 diabetes

Daniela Jakubowicz et al. Diabetes Care. Doi: 10.2337/dc15-0761

Breakfast – most important meal of the day or something to miss with minimal impact on glycaemia? Missing breakfast has been consistently linked with post prandial hyperglycaemia and elevated HbA1c in patients with Type 2 diabetes. This elegant cross over study (albeit of only 22 patients) looked at the metabolic changes resulting from a missed breakfast. Compared with patients who had breakfast, patients who missed it had significantly higher lunch and dinner post prandial glucose, free fatty acid and glucagon whilst their GLP1 and insulin levels were lower. Furthermore, the insulin peak was delayed 30 min after lunch and dinner when breakfast was missed. Overall, missing breakfast resulted in metabolic changes which persisted throughout the day. This study does reinforce the importance of breakfast on glycaemic control although the type of food eaten at the start of the day will also have an impact, for example calorie content, glycaemic index etc – not examined in this study.

http://care.diabetesjournals.org/content/early/2015/07/01/dc15-0761.short

https://www.glycosmedia.com/9428-2/

Admission blood glucose predicts mortality and length of stay in patients admitted through the emergency department

Martin WG, Galligan J et al.  Internal Medical Journal. Doi: 10.1111/imj.12841

The need to control blood glucose levels in patients with acute illness in hospital is well established and  has lead to the development of guidelines for these patients especially the recognition that referral to the inpatient diabetes team is necessary. However, patients without a diagnosis of diabetes often present with hyperglycaemia, possibly due to unrecognised diabetes or stress hyperglycaemia. This retrospective observational study showed that an admission glucose >11.5mmol/l was significantly associated with increased 90 day mortality in those patients without a diagnosis of diabetes. This was not the case in those patients with a diagnosis – although their length of stay was longer. There is a need to recognise the importance of glycaemic control in all patients, not just those with diabetes – as well as to review their glycaemic status after discharge because of the long term implications of missing a diagnosis of diabetes.

http://onlinelibrary.wiley.com/doi/10.1111/imj.12841/abstract

 

Metformin versus insulin for gestational diabetes mellitus: a meta-analysis

Zhao LP, Sheng XY et al.  British Journal of Clinical Pharmacology. Doi: 10.1111/bcp.12672

Gestational diabetes is associated with an increased risk of a variety of maternal and perinatal complications including macrosaomia, shoulder dystocia and respiratory distress. Until comparatively recently, the only drug used to manage hyperglycaemia in gestational diabetes was insulin.  However, in keeping with clinical practice, recent NICE guidance promotes the use of Metformin in the treatment of hyperglycaemia even though it crosses the placenta and reaches pharmacological levels in the foetus. As such, there is always a nagging doubt about its safety despite studies suggesting otherwise. Its safety is reinforced by this meta-analysis of 8 studies which showed no clinically relevant safety or efficacy difference when compared to insulin although it was associated with a lower incidence of pregnancy induced hypertension. It also has the advantage of being an oral agent as well as being weight neutral. However, its use should also accompany lifestyle changes – often harder to prescribe.

http://onlinelibrary.wiley.com/doi/10.1111/bcp.12672/abstract

 

Case–control study of second-line therapies for type 2 diabetes in combination with metformin and the comparative risks of myocardial infarction and stroke

Floyd JS, Wiggins JL et al. Diabetes, Obesity & Metabolism. DOI: 10.1111/dom.12537

After lifestyle modification, it is universally accepted that Metformin is the drug of choice. However the second line agent of choice remains a subject for discussion with sulphonylureas appearing prominently. Since the concerns about Rosiglitazone, there has been an increasing emphasis on the cardiovascular safety of anti-diabetic drugs. Pioglitazone and the DPP 4 inhibitors have been shown to have no negative CV impact with studies examining SGLT2 inhibitors and GLP1 analogues in progress.  Insulin has been considered a ‘clean drug’ from a CV point of view. The issue with sulphonylureas has been debated for many years and indeed a metanalysis in 2013 suggested that sulphonylurea use may elevate the risk of cardiovascular disease among patients with diabetes. However, this study suggests that there may not be large differences in cardiovascular risk associated with the use of insulin or sulphonylureas when used in combination with Metformin. Whatever the current evidence, large prospective studies are unlikely and given the decades of experience with sulphonylureas, they seem set to remain in guidelines of all varieties.

http://onlinelibrary.wiley.com/doi/10.1111/dom.12537/abstract

 

Inhaled Technosphere insulin compared with injected prandial insulin in type 1 diabetes

Bruce W. Bode et al.  Diabetes Care. Doi: 10.2337/dc15-0075

 Inhaled insulin was available for use in the UK in 2006 when Pfizer launched ‘Exubera’ but it did not do well. NICE quickly limited its use by recommending that it should only be considered for people with an injection phobia (confirmed by a psychiatrist or psychologist!) or those with ‘severe persistent problems with injection sites’. In addition, the inhaler device was large and clumsy and then came lawsuits in the US suggesting that it might be linked with lung malignancy. Exubera was withdrawn from the market in 2007 and phase 3 trials of similar (but better) products from Lilly and Novo Nordisk were promptly terminated.  However, all was not lost. Mannkind continued the development of inhaled insulin and, following an agreement with Sanofi, this was launched in the US last year as ‘Afrezza’. This paper describes how the inhaled insulin provides equivalent glycaemic control to meal-time injections, with less hypoglycaemia and weight gain. Cough was an expected side-effect. Initial sales of Afrezza in the US have been disappointing and so its future is uncertain. It remains to seen whether a UK launch will happen.

http://care.diabetesjournals.org/content/early/2015/07/08/dc15-0075.abstract

 

Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes

Kunihiro Matsushita et al. Lancet Diabetes & Endocrinology. Doi: http://dx.doi.org/10.1016/S2213-8587(15)00040-6

Although eGFR is regarded as a test for chronic kidney disease (CKD), the chance of a person with T2DM and stage 3 CKD progressing to end-stage renal failure is vanishingly small. Reduced eGFR is highly correlated with CV disease and should be regarded a CV marker. The second ‘CKD screening’ tool, until recently enshrined in GMS diabetes practice, is urinary albumin excretion, assessed by a urine albumin-to-creatinine ratio (UACR) on a first voided sample. The presence of microalbuminria (elevated albumin excretion but below that detectable by routine dipstick testing) was reported to predict diabetic nephropathy in patients with T1DM and quickly adopted for renal screening in all diabetes populations. However, in T2DM, it predicts CV risk much better than renal deterioration. So, the two major CKD screeners are actually CV screening tests. The does mean that their annual assessment in patients with established CVD is of questionable value.

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00040-6/abstract

 

https://www.glycosmedia.com/9336-2/

Metformin use and mortality in patients with advanced chronic kidney disease

Hung SC, Chang YK.  Lancet Diabetes & Endocrinology. Doi: http://dx.doi.org/10.1016/S2213-8587(15)00123-0

One of the (very few) internationally agreed guidance is that Metformin should be the first line oral hypoglycaemic agent after lifestyle changes. However, its link with lactic acidosis in impaired renal function has led to its use being cautioned if eGFR 30-45 and withdrawn when eGFR<30 (NICE). Recent evidence however suggests that its safety continues with increasingly significant renal disease, CKD 3-4. However, there is less evidence for those with CKD 5 (creatinine >530 μmol/L). Retrospectively, 2 groups of T2DM patients with chronic kidney disease were matched for 30 baseline characteristics. Whilst after multivariate analysis, those on metformin had a significantly higher mortality in a dose dependent manner; interestingly there was no significant difference in the incidence of lactic acidosis. Given that most patients in the UK will have had their metformin stopped significantly earlier in the progression of CKD than this group, this paper is unlikely to influence clinical practice.

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00123-0/fulltext

 

Euglycaemic Diabetic Ketoacidosis: A Potential Complication of Treatment with Sodium-Glucose Cotransporter 2 Inhibition

Peters A, Buschur E. Diabetes Care. Doi: 10.2337/dc15-0843

Recently, increasing interest has arisen around using a number of agents in conjunction with insulin for patients with Type 1 diabetes. Indeed, the draft NICE guidance recommends the use of metformin in overweight T1 patients. The most recently approved agents, the SGLT2 inhibitors should, given their non insulin mediated method of action, be effective. However, recent reports have suggested a possible link with euglycaemic diabetic ketoacidosis. This paper identifies 13 cases of euglycaemic DKA in 9 individuals (7 T1DM). The absence of hyperglycaemia delayed presentation in most cases. Theories for this include hyperglucagonaemia, noninsulin-dependent glucose clearance, volume depletion or reduction of insulin doses after the SGLT2 was added. SGLT2 inhibitors should clearly only be used with great care in patients with T1DM and after the patient has been counselled and given the ability to check for blood/ urine ketones.

http://care.diabetesjournals.org/content/early/2015/06/03/dc15-0843.abstract

 

Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes

Rodney A. Hayward et al. NEJM. Doi: 10.1056/NEJMoa1414266

This is another study, which emphasises that control of hyperglycaemia takes a long time to manifest as cardiovascular benefit in people with type 2 diabetes (T2DM). The Veterans Affairs Diabetes Trial (VADT) previously showed that intensive glucose lowering did not significantly reduce the rate of major cardiovascular events among 1791 military veterans with median follow-up of 5.6 years. Using central databases, the authors achieved follow-up of 77.7% of participants for a further five years, making 10 years in total. Within three years of the original study completion, the difference in HA1c between the intensive and standard-therapy groups had fallen from 1.5% to less than 0.3%. However, the intensive-therapy group at the end of follow-up had significantly lower risk of the primary outcome (hazard ratio, 0.83; 0.70-0.99; P=0.04). They did not, however, have reduced cardiovascular mortality, nor a reduction in total mortality. So, whilst (as in the UKPDS) a ‘legacy effect’ is shown, it takes a long time to become apparent and the current NICE guidelines, which allow for sub-optimal glycaemia early in the course of T2DM may not be ideal.

http://www.nejm.org/doi/full/10.1056/NEJMoa1414266

 

Cardiovascular mortality in type 2 diabetes patients with incident exposure to insulin glargine

Sorin Loacara et al. Journal of Diabetes Research. Doi: http://dx.doi.org/10.1155/2015/962346

This article is of interest since it suggests that use of basal analogue insulin (glargine) in people with type 2 diabetes (T2DM) is associated with lower cardiovascular (CV) risk. Although the reported benefit was small, (a subhazard ratio of 0.963 with confidence intervals approaching unity i.e. non-significance), it is further evidence for the CV safety of insulin. This had previously been questioned and was a major reason for the execution of the United Kingdom Prospective Diabetes Study (UKPDS). These latest data are also consistent with the findings of the ORIGIN trial, which showed no increased CV risk despite very early glargine initiation (12% of participants had pre-diabetes). An interesting observation from ORIGIN was the extremely tight control maintained by participants over the seven years of study, along with high levels of compliance and low rates of hypoglycaemia. This highlights the potential for early use of insulin in the treatment of some T2DM patients, and yet the latest draft of the NICE guidelines continues to position it as treatment of almost last resort. Yet another plea for flexibility in guideline

http://www.hindawi.com/journals/jdr/2015/962346/

 

Comparative efficacy and safety of blood pressure-lowering agents in DKD

Suetonia C Palmer et al. Lancet. Doi: http://dx.doi.org/10.1016/S0140-6736(14)62459-4

Busy medical professionals often don’t get past the abstract of an article, so what will they make of this network meta-analysis (NMA), published in the Lancet. Headlines are; ‘no drug regimen was more effective than placebo for reducing all-cause mortality’ and ‘compared with placebo, end-stage renal disease was significantly less likely after dual treatment with an angiotensin-receptor blocker (ARB) and an angiotensin-converting-enzyme (ACE) inhibitor’. Furthermore, ‘no regimen significantly increased hyperkalaemia or acute kidney injury’. Diabetes clinicians will cite dominance of blood pressure control over glycaemia and point to MHRA warnings against use of ARB and ACE combinations because of the increased risk of hyperkalaemia and impaired renal function. So, how could these conclusions have been reached? I believe this is yet another example of NMA (which compares treatment effects from different studies – termed ‘transivity’), being able to prove that nothing (here literally) is better than anything else. It is important since NICE is now wedded to NMA and can use it to demonstrate that all treatments are equal (so use the cheapest). My thoughts – stick with the results of large randomised clinical trials.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62459-4/fulltext

 

 

https://www.glycosmedia.com/9171/

Effectiveness of peer support for improving glycaemic control in type 2 diabetes

Li Qi, Qin Liu et al. BMC Public Health. Doi: 10.1186/s12889-015-1798-y

This fascinating paper from China offers an impressive non pharmacological approach to improving diabetic control in type 2 diabetes. Utilising peer support, this study showed that “a pooled mean reduction of 0.57% in HbA1c levels compared with usual care”. This meta-analysis managed to find 13 randomised controlled trials which covered over 2300 patients. Interestingly, those less well controlled seemed to benefit more than their better controlled counterparts. As well as being innovative, this may provide a cost effective contribution to the management of diabetes in some groups of people. Most of the 13 trials were based within the United States, which means more research is needed to assess its suitability in other countries such as the UK. Not only that, we need to be more precise on what is the most effective form of peer support. The paper also mentions telephone based peer support and this could be another suitable intervention. I would guess peer support could offer an attractive option as a relatively low cost solution to manage the ever expanding diabetic workload. But we need more proof of effectiveness.

http://www.biomedcentral.com/1471-2458/15/471

 

A decade in diabetes specialist services, 2000 to 2011, in England

C.A. Gosden, K. Barnard et al. Diabetic Medicine. Doi: 10.1111/dme.12786

As a GP witnessing perpetual change in our NHS working environment, I find fascinating to observe the view from specialist services. The results are not that surprising but good to see that efforts have been made to verify staff views and this was obtained through interviews. Analysis of the results concluded that people are prepared to accept change and admire the workings of a multidisciplinary team. However the ongoing organisational working pattern changes have had a corrosive effect on morale, as working relationships and team building are disrupted. Admittedly these results are based on a relatively small sample but they make sense and probably chime with many NHS workers’ feelings. Lack of resources was quoted as an issue and I am sure that remains relevant to today’s climate. I am sure these results apply not to just diabetic services but it would be good to see this work replicated elsewhere in other specialities with greater numbers. From my perspective as a GP, I can see many similarities in primary care to the concerns expressed by the diabetic team.

http://onlinelibrary.wiley.com/doi/10.1111/dme.12786/abstract

 

MicroBiome therapeutics receives positive response from FDA for diabetes drug NM505

PRN Newswire.

There is increasing interest in how changes in bowel microbiota might be linked to metabolic diseases such as obesity, cardiovascular disease and type 2 diabetes (T2DM). This has been fuelled by publication of a genetic analysis of bowel microbes showing differences in women with normal, impaired and glucose intolerance and the intriguing report of a patient becoming obese after receiving a faecal transplant for treatment of Clostridium difficile infection. There have been suggestions that the epidemic of T2DM can be explained by changes in the bowel microbiome (i.e. it is a major environmental factor) and that the glycaemic impact of bariatric surgery is related to alterations in gut microbes. This study reports on another way in which the microbiome may be involved in T2DM. NM505 is a proprietary combination of a microbiome modulator and metformin, the most widely prescribed first-line therapy worldwide for T2DM. Unfortunately metformin is often poorly tolerated, due to gastro-intestinal side-effects. This proof-of-concept study showed that NM505 improved the tolerability of metformin while further reducing blood glucose levels, introducing the possibility of revisiting metformin use in previously intolerant patients.

http://www.prnewswire.com/news-releases/microbiome-therapeutics-receives-positive-response-from-fda-for-use-of-expedited-regulatory-pathway-for-diabetes-drug-nm505-300081615.html

 

Diabetes complications at presentation and one year by glycated haemoglobin at diagnosis in a multiethnic and diverse socioeconomic population: results from the South London Diabetes StudyAzam M, Marwood L. Journal of Diabetes Research. Doi: http://dx.doi.org/10.1155/2015/587673

The use of a cut off HbA1c of ≥48mmol/mol has been introduced following several publications linking HbA1c and diabetes related complications, specifically retinopathy. Its use has also been adopted as the measurement of plasma glucose (fasting or during a glucose tolerance test) has been considered inconvenient. However, given that its levels can be affected by non glycaemic issues, there may be concerns as to whether it enables diagnosis of all patients with diabetes. This multiethnic South London study compared patients previously diagnosed with diabetes using glucose status with HbA1c < and > 48mmol/mol. In this cohort, 22% of people previously diagnosed with T2DM would not be deemed diabetic, where HbA1c was the sole diagnostic criterion. These people were older at diagnosis and more likely to be of white ethnicity. They were also more likely to have been asymptomatic at diagnosis. Delayed diagnosis may be clinically relevant due to the development or progression of complications. Whilst HbA1c >48 is diagnostic, a result <48mmol/mol cannot be taken as conclusive evidence to exclude T2DM.  It is also worth pointing out that WHO state that a diagnosis based on glucose measurements trumps an HbA1c<48mmol/mol.

http://www.hindawi.com/journals/jdr/2015/587673/

 

High strength, fixed combination and biosimilar insulin products: minimising the risk of medication error

Medicines and Healthcare Products Regulatory Agency. 29 April 2015

Until recently, the vast majority of insulin preparations were in the concentration of U100 (100 units/ml). However, several new high strengths insulins are now on the market including U200 insulin Degludec, U200 Humalog and U300 Lantus. These insulins have been developed for patients with large daily insulin requirements to reduce the number and volume of injections. As a result, a new term ‘the dose step’ has been developed to enable patients to appropriately dial up their required insulin dose. For original U100 Lantus, U300 Lantus, U100 Degludec and both strengths of Humalog (U100 and U200), one dose step is equivalent to one unit of insulin whilst for Degludec, one dose step on the U200 is equivalent to two units of insulin. Advice is given in this update from the European Medicines Agency to health care professionals as to how to help patients starting or transferring onto these new insulins including education, dose adjustment and blood glucose monitoring.

https://www.gov.uk/drug-safety-update/high-strength-fixed-combination-and-biosimilar-insulin-products-minimising-the-risk-of-medication-error

https://www.glycosmedia.com/9039/