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.
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.
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.
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?
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.