Chronic Kidney Disease (CKD) is a long-term irreversible deterioration in the function of the kidneys often found in patients who also have diabetes and high blood pressure (HQIP)
Archives for January 2017
Glyburide and metformin are comparable oral treatments for GDM regarding glucose control and adverse effects. Their combination demonstrates a high efficacy rate with a significantly reduced need for insulin, with a possible advantage for metformin over glyburide as first-line therapy (Diabetes Care)
2016 has seen the publication of two large type 2 diabetes (T2DM) cardiovascular safety outcome trials (CVOTs) which showed benefit of glucagon-like receptor-1 agonists (GLP-1RAs). The LEADER study compared once-daily liraglutide with placebo in over 9,000 patients treated for a median of 3.8 years and showed statistically significant superiority in the primary end-point of a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The SUSTAIN 6 study was a smaller (3,297 patients), shorter (104 weeks) pre-license analysis of once-weekly semaglutide versus placebo. Using the same primary end-point, it demonstrated superiority, albeit in an analysis which was not pre-specified; for this reason, a further much larger CVOT of injected semaglutide is anticipated.
GLP-1RAs are currently administered by subcutaneous injection and, although this is a very simple procedure, it does act as a barrier to their early inclusion in therapy algorithms. Indeed, in the NICE T2DM guideline, published in December 2015, this class of anti-diabetes therapy is restricted to the pre-insulin segment and only after failure of triple oral therapy. However, there is rapid progress being reported in this field. In December 2016, vTv Therapeutics Inc. announced positive data from a phase 2 study evaluating TTP273, an oral small molecule GLP-1RA. TTP273 demonstrated a statistically significant reduction in HbA1c with negligible incidence of nausea and vomiting, the most common side-effects of GLP-1RA administration. A trend towards weight loss was also observed.
The development of an oral version of semaglutide is even more advanced. This once-daily GLP-1RA is currently going through an extensive phase 3 programme, having demonstrated impressive reductions of both HbA1c (of almost 2.0%) and weight (up to 6.5Kg) in the phase 2 trials. The pre-license CVOT of oral semaglutide, known as PIONEER 6 is due to recruit its first patients in January 2017.
So, there is the prospect of oral GLP-1RAs, with superior CV profiles to established anti-diabetes therapies. And these follow-on from the results of the EMPA-REG OUTCOME study which showed CV superiority of oral empagliflozin over placebo, once again using the primary end-point used in LEADER and SUSTAIN 6. Moreover, this sodium-glucose 2 transporter (SGLT2) inhibitor also dramatically reduced heart failure admissions, something not seen with GLP-1RAs. A caveat for all three studies is that only patients at extremely high-risk of CV disease were included and so their generalisablity to all patients with T2DM has yet to be demonstrated. More studies, currently on-going, will help address this question (e.g. the CANVAS study of canagliflozin, due to publish in 2017).
The EMPA-REG OUTCOME data has, however, led the FDA to approve a new indication for empagliflozin ‘to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and cardiovascular disease’. The 2017 American Diabetes Association Guidelines will include a new recommendation ‘to consider the use of empagliflozin in people with type 2 diabetes and established cardiovascular disease to reduce the risk of cardiovascular death’. And other national guidelines, such as those of the Canadian Diabetes Association, have already made changes based on these data.
The question remains as to how these developments will be integrated into guidance in the UK. The 2015 NICE update came over six years after its previous iteration and it almost didn’t include any reference to the SGLT inhibitors, despite the first of them being licensed for use in the EU in 2012. The full guideline assessment by NICE is clearly too slow, something acknowledged by the agency when Clinical Guideline 28 was launched, however, the process for early updating has not been disclosed. The therapy landscape is rapidly changing and this issue needs to be addressed.
Professor Steve Bain
In 2015, Public Health England commissioned four sets of questions on NatCen’s British Social Attitudes (BSA) survey, one of which focused on obesity. The BSA is an authoritative, high quality source of data on views of the British public which has been performed annually since 1983. It uses random probability sampling to yield a representative sample of adults aged 18 years and older who live in private households. The majority of questions are asked by an interviewer face-to-face in the form of a Computer Assisted Personal Interview, while a smaller number are answered by respondents in a self-completion booklet.
“Attitudes to obesity” is the publication of the obesity findings from the 2015 survey, presenting new findings on attitudes towards obesity and what might be done to reduce its prevalence. Despite appreciating some of the health risks, people tended not to recognise obesity when present, especially in men. Obesity was typically regarded as a problem for individuals and health care professionals rather than society in general. Furthermore, those who are obese were often stigmatised.
The findings are particularly relevant to type 2 diabetes (T2DM) since obesity is widely seen as the driver behind the T2DM ‘epidemic’. Regarding obesity as individual issue, implies that people are personally responsible for their plight and this is then extrapolated to blame following a diagnosis of T2DM. In this environment, the political imperative to allow for new ‘expensive’ treatments to be made available to people with T2DM is low. Indeed, a new definition of ‘expensive’ comes into play, where the individual per-person drug cost is subsumed by the population cost because of the large numbers involved. On this basis, one can argue that people with T2DM are discriminated against, compared with other conditions such as cancer, heart disease and liver disorders.
Fortunately, the survey showed significant support for actions aimed at reducing levels of obesity. We need to make sure that our patients with T2DM can also tap into this support.
Professor Steve Bain
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.
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 HbA1c ≥5.7% as in those with HbA1c ≤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.
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.
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
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.
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.
Future research should concentrate on targeting lipids with one or more aggressive interventions specifically in patients with DM2 whose DPN is detectable but whose progression can still be largely prevented (Journal of Diabetes Research)
This document summarises the evidence-base on safer insulin prescribing. It is a key therapeutic topic which has been identified to support medicines optimisation. It is not formal NICE guidance (NICE)
These findings show that glucose homeostasis is altered from illness onset in schizophrenia, indicating that patients are at increased risk of diabetes as a result. This finding has implications for the monitoring and treatment choice for patients with schizophrenia (JAMA)
The model indicates that diabetes prevention interventions are likely to be cost-effective and may be cost-saving over a lifetime. In the model, the criteria for selecting at-risk individuals differentially impact upon diabetes and cardiovascular disease outcomes, and on the timing of benefits. These findings have implications for deciding who should be targeted for diabetes prevention interventions (Diabetic Medicine)
The association of S/P with the metabolic status of obese individuals was further validated in a cross-sectional cohort of 381 participants. In summary, higher baseline S/P was associated with greater probability of diabetes remission after RYGB and may serve as a diagnostic marker in preoperative patient assessment (FASEB)
This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion and relevant references to the literature (Diabetes Care)
We found conflicting findings of temporal trends of US adolescent prediabetes prevalence based on the ADA’s prediabetes criteria. The increasing prevalence of prediabetes by HbA1c assessment is concerning and raises the urgency for increased awareness and appropriate measures of prediabetes status among physicians and patients (Acta Diabetologica)
Basal-bolus insulin in the inpatient diabetes management results in significantly lower mean daily BG than sliding scale insulin but is associated with increased risk of mild hypoglycemia (Diabetes/Metabolism Research and Reviews)
In this manuscript, we discuss the evidence supporting different BP targets in diabetics and review the various guidelines on this topic. In addition, we discuss the various options available for the treatment of hypertension in diabetics and the recommendations for a specific treatment over the other. Finally we briefly discuss the new diabetic drug classes and their influence on (Cardiovascular Diabetology)
There were no relationships between baseline HbA1c levels or HbA1c levels following 1 month of treatment and the risk of MACE events. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS (Diabetes, Obesity and Metabolism)
The present study showed that GA/HbA1c ratio was significantly associated with the presence and severity of NAFLD on US (Diabetes Research and Clinical Practice)
Liraglutide 1.2 mg is likely to be considered cost-effective versus alternative daily administered GLP-1 receptor agonists for treatment of type 2 diabetes in the UK (Diabetes Therapy)
These findings suggest that “screen and treat” policies alone are unlikely to have substantial impact on the worsening epidemic of type 2 diabetes (BMJ)
Importance for the Development of New Therapies
Weight reduction in patients with diabetes can be maintained for 5 years and is predicted by patients’ ability to maintain ≥7% weight loss at 1 year. A1C and triglycerides deteriorate with weight regain, while other lipid improvements are maintained. Sustained weight loss is associated with significantly lower A1C for 5 years and lowers BP for 18 months (BMJ)