The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use (BMJ)
Archives for February 2016
Although insulin is essential for the survival of people with type 1 diabetes and is needed for improved management of diabetes for some people with type 2 diabetes, very little has been done globally to address the issue of access, despite the UN’s political commitment to address non-communicable diseases and ensure universal access to drugs for these disorders (The Lancet Diabetes & Endocrinology)
Besides preventing a modest negative effect of n-3 fatty acids on glycemic control, the combination of pioglitazone and EPA + DHA can be used to improve lipid metabolism in T2D patients on stable metformin therapy (Medscape) – Registration required
The findings expand and refine our understanding of SGLT2 and its inhibition, have relevance for clinical practice, and will help interpret ongoing clinical trials on the long-term safety and cardiovascular effects of SGLT2 inhibitors (Medscape) – Registration required
Low dose basal insulin infusion as a percentage of total insulin dose has a positive effect on metabolic outcome as expressed in HbA1c-levels. A change of 10% in %BD/T results in a decrease or increase of HbA1c of 0.22%. This supports the tendency to aim at the lowest basal insulin requirements in pump setting strategy (Pediatric Diabetes)
Our data suggest that metformin accumulation contributes to the pathogenesis and prognosis of lactic acidosis (Diabetic Medicine)
Training practice-based staff to provide foot assessments in primary care ensured that the specialist podiatry service had the capacity to provide the necessary care and treatment for those at higher risk of developing diabetic foot problems (NICE)
Diabetes has been recognised as a risk factor in pregnancy for many years – indeed the need to reduce this risk was a pillar of the St Vincent declaration in 1989. Adverse outcomes were highlighted in the Confidential Enquiry into Maternal and Child Health report (CEMACH) in 2003 which has been followed by two cycles of NICE guidance in 2008 and 2015. The second (2014) National Diabetes in Pregnancy audit (NPID) gives a snapshot of the current levels of care in England and Wales by reviewing 2553 pregnancies from 150 sites – a significant increase from the initial 2013 audit. Both the national audits show a significant increase in the number of women with T2DM becoming pregnant compared with 2003 probably due to the rise in pregnancies from high risk ethnic groups including S Asians.
Unfortunately, despite a plethora of evidence, women continue to be poorly prepared for pregnancy with many becoming pregnant whilst taking potentially teratogenic drugs including ACE inhibitors. More than 50% of women were not taking the recommended higher dose (5mg) of folic acid. Pre-conceptual glycaemic control was also sub-optimal with only 15% of T1 and 35% of T2 patients having HbA1c <48mmol/mol. Whilst maternal care may remain an issue, with approx 10% of women in hospital having at least one hypo, there has been an improvement in the numbers of emergency sections since 2003 (30 vs 37%) although this still remains higher than the general population. The improvement is likely to be due to NICE recommendation about delivery at 38 weeks. Macrosomia also remains common, affecting one third of all babies, predominantly T1 patients, an issue exacerbated by poor control in the third trimester.
Overall, the NPID shows a modest improvement in outcomes since 2003. Engagement is clear from the number of centres submitting data but women are still being poorly prepared for pregnancy and outcomes have changed little since the 2003 CEMACH report. Given the change in epidemiology of pregnancy complicated by diabetes, both this and the initial 2013 audit should serve as a guide to health care professionals, commissioners and trusts as to making improvements in care. Clearly there remains a long way to go before the aims of the St Vincent declaration can be satisfied.
Dr Mark Freeman
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.
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.
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….
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.
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.
This study showed that women with GDM had significantly increased cholesterol levels, triacylglycerol levels, TG/HDL-C ratios, LDL-C/HDL-C ratios, and fasting glucose levels during early pregnancy. Moreover, early pregnancy cholesterol levels, triacylglycerol levels, TG/HDL-C ratios, LDL-C/HDL-C ratios, and fasting glucose levels were associated with GDM risk (Journal of Diabetes Research)
EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has finalised a review of SGLT2 inhibitors (a class of type 2 diabetes medicines) and has made recommendations to minimise the risk of diabetic ketoacidosis (EMA)
Evidence-based recommendations on the MiniMed Paradigm Veo and Vibe and G4 PLATINUM CGM sensor-augmented pump therapy systems, which combine continuous glucose monitoring and continuous subcutaneous insulin infusion, for people with type 1 diabetes (NICE)
In this population-based cohort of overweight patients with type 2 diabetes, successful therapeutic intentional weight loss, supervised by a doctor over six years, was not associated with reduced all-cause mortality or cardiovascular morbidity/mortality during the succeeding 13 years (PLoS ONE)
This algorithm for the comprehensive management of persons with type 2 diabetes was developed to provide clinicians with a practical guide that considers the whole patient, their spectrum of risks and complications, and evidence-based approaches to treatment (AACE/ACE)
Prediabetes appeared to be less associated with cardiovascular disease in the South Asian than in the European group. These findings have implications for screening, and early cardiovascular prevention strategies in South Asian population (Diabetic Medicine)
Optimal glycaemic control close to diagnosis persists several years after diagnosis and this metabolic memory seems to be enhanced by the use of set blood glucose targets. Heather Thom and colleagues at NHS Tayside describe their initiative to introduce insulin adjustment for blood glucose and carbohydrate meal content from the first day of diabetes diagnosis in children (Practical Diabetes)
Currently GLP-1 analogues are not licensed for T1DM, but early trial evidence suggests a role for this drug class in weight reduction and improved glycaemic control. Helen Partridge and colleagues at the Bournemouth Diabetes Centre analyse HbA1c and weight change data from their patients with type 1 diabetes when a GLP-1 analogue was added to pre-existing treatment (Practical Diabetes)
A large evidence base supports the use of statins in people with type 2 diabetes, but there is very limited evidence for the use of statins in people with type 1 diabetes. Cardiovascular expert, Miles Fisher examines the confusion and contradictory recommendations from major guidelines, highlights the lack of new data and suggests a pragmatic approach based upon the existing research (Practical Diabetes)
Six points including: Optimizing glycemic control before surgery, not withholding basal insulin on the morning of surgery, and keeping the patients on insulin intravenous infusion protocols in the perioperative period are necessary to prevent postoperative DKA in patients with severe diabetes (Diabetes Care)
Evolocumab markedly reduces atherogenic lipoproteins in patients with type 2 diabetes, an effect that is consistent across subgroups and similar to that seen in patients without type 2 diabetes (The Lancet Diabetes & Endocrinology)