The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol (JAMA)
Archives for 2016
Administration of DPP-4i reduces urine albumin excretion and mitigates reduction of eGFR in T2DM patients (Journal of Diabetes Research)
A 12-week treatment with liraglutide or sitagliptin only resulted in a brief and modest increase of plasma pancreatic enzyme concentrations in patients with type 2 diabetes. Apart from a minimal sitagliptin-induced increase in intraduodenal fluid secretion, pancreatic exocrine function was unaffected (Diabetes Care)
To determine the clinical trial representation of black or African American people, we reviewed the published data from the seven cardiovascular outcome trials instigated by the 2008 FDA mandate for evaluating cardiovascular risk for new therapies in type 2 diabetes (The Lancet Diabetes & Endocrinology)
With respect to treatment choice, data from this study supports the notion of prescribing beyond M+SU, as alternative regimens have been demonstrated to be associated with reduced outcomes risk and value for money (Diabetes, Obesity and Metabolism)
The MM represents an alternative approach to simulate HbA1c trajectories in T2DM models, since UKPDS data may not adequately reflect the heterogeneity of HbA1c profiles observed in clinical studies. However, the choice of approach should ultimately be determined by the characteristics of individual patients under consideration, and the clinical face validity of the modelled trajectories (Diabetes, Obesity and Metabolism)
70 poems from Jim Young, editor-in-chief, Glycosmedia.
This is an easy and wide-ranging read that will stir your emotions.
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If you love poetry – then you will love this book.
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He is making a parse at you, and you alone.
Available from Amazon https://www.amazon.co.uk/dp/1541310357
Jim Young (author)
The biological effect of this vaccination should be developed further in order to reach clinically desirable reductions in insulin loss in patients recently diagnosed with type 1 diabetes (Diabetologia)
These results show that within families with a young child with Type 1 diabetes, the burden of care increases in fathers and decreases in mothers, suggesting that fathers assume more responsibility for care of their child with Type 1 diabetes as the child grows (Diabetic Medicine)
In light of the American Diabetes Association’s (ADA’s) new position statement on psychosocial care in the treatment of diabetes, the “Standards of Medical Care in Diabetes,” referred to as the “Standards of Care,” has been updated to address psychosocial issues in all aspects of care including self-management, mental health, communication, complications, comorbidities, and life-stage considerations (Diabetes Care)
Continuous glucose monitoring (CGM) has an important role in assessing the effectiveness and safety of treatment in subgroups of patients with type 1 diabetes and in selected patients with type 2 diabetes (Diabetes Care)
Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas (Lancet)
Fear of self-injecting and fear of self-testing are common among adolescents with T1DM. Therefore, it is essential to ensure comprehensive multidisciplinary diabetes education to lower the risk factor of fear of injections (Diabetes Therapy)
Initiation of insulin, compared with DPP-4i treatment, was associated with an increased risk of subsequent all-cause mortality, fatal and nonfatal CVD, and severe hypoglycemia. Results from randomized trials will be important to elucidate causal relationships (Diabetes Research and Clinical Practice)
A Position Statement by the American Diabetes Association (Diabetes Care)
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.
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.
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?
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.
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.
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.
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.
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.
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.
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.
Metformin, a drug which is now universally accepted as the first line pharmacological treatment for Type 2 diabetes does have a recognised list of side effects and cautions. These include gastrointestinal symptoms and guidance regarding renal function. Indeed, NICE advise a dose reduction in patients whose eGFR falls to between 35-40 and to discontinue when eGFR falls below 30 (although there is evidence to suggest that it is safe in patients with lower values). However, there are other less well known issues which are often not recognised. Lactic acidosis, myalgia and taste disturbance are not uncommon. However, despite being recognised in 1969, the impact of Metformin on Vitamin B12 levels is often poorly recognised or ignored. Vitamin B12 is a water-soluble vitamin that plays a very fundamental role in DNA synthesis, optimal haemopoesis and neurological function. As a result, vitamin B12 deficiency presents with features of haematological and neuro-cognitive dysfunction. Decrease in vitamin B12 absorption and levels following Metformin use typically starts as early as the 4th month. Clinically overt features of vitamin B12 deficiency manifest by 5–10 years owing to the large body stores in the liver mainly that are not quickly depleted. The proposed mechanisms to explain Metformin induced vitamin B12 deficiency among patients with T2DM include: alterations in small bowel motility which stimulates bacterial overgrowth and consequential vitamin B12 deficiency, competitive inhibition or inactivation of vitamin B12 absorption and alterations in intrinsic factor (IF) levels. Metformin has also been shown to inhibit the calcium dependent absorption of the vitamin B12-IF complex at the terminal ileum. This inhibitory effect is reversed with calcium supplementation. Recent evidence regarding the impact of Metformin on B12 comes from paper in a recent issue of JCEM. The study reviewed patients previously enrolled in the diabetes prevention programme where the Metformin arm received 850mg bd. After 5 years of the study, low B12 levels affected 4.3% of the Metformin group and 2.3% of the placebo group. Those taking Metformin were more likely to have anaemia, regardless of their B12 status whilst those patients with low B12 were more likely to have a peripheral neuropathy. Given the link between Metformin and B12 deficiency and its clinical impact, patients should have their B12 intermittently measured and replaced if found to be low.
Dr Mark Freeman
NICE guidance (NG28) released on 15th December 2015 changed the advice regarding aspirin use to: ‘Do not offer antiplatelet therapy (aspirin or clopidogrel) for adults with type 2 diabetes without cardiovascular disease.’ This has raised the question as to whether patients already taking aspirin, in line with the previous NICE clinical guideline (CG87), should now stop (although NICE did not specifically recommend this action).
The guideline development group for NG28 focused on three studies of antiplatelet therapies, two of which provided new evidence. One was an unpublished post-hoc analysis of cardiovascular (CV) outcomes in the Early Treatment Diabetic Retinopathy Study and the second from a Japanese population, with notoriously low levels of CV events. The doses of aspirin used ranged from 61-650 mg, and the quality of the evidence was rated as between ‘moderate’ and ‘very low’.
New, high quality evidence will appear in the near future. NICE acknowledged the UK-based ASCEND trial, which includes 15,480 people with diabetes without occlusive arterial disease, which is scheduled to continue until 2017. NICE also highlighted another trial (ACCEPT-D) conducted in Italy which also aims to assess the effects of low-dose aspirin on major vascular events in people with diabetes and no clinical evidence of vascular disease. For this reason, NICE did not recommend further research in this area.
Other guidelines do not support change. The American Diabetes Association ‘Standards of Care’ 2016 continues to recommend consideration ‘of aspirin therapy (75–162 mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes who are at increased CV risk (10-year risk >10%). This includes most men or women with diabetes aged 50 years who have at least one additional major risk factor’- remarkably similar to CG87.
There is also evidence in the literature of a rebound effect from stopping aspirin i.e. an increased risk of ischaemic stroke in patients four weeks after discontinuation. Furthermore, duration of aspirin use is not a risk factor for bleeding, that is to say those patients who are established on aspirin are at low risk of its major side-effect.
This balance of risks should make practitioners very wary of change.
Professor Steve Bain
With lower basal insulin levels, lower HbA1C was achieved despite the same total bolus dose. The optimal basal dose as determined by this study is similar to that found in fasting individuals of similar age (The Journal of Pediatrics)