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However, its link with lactic acidosis in impaired renal function has led to its use being cautioned if eGFR 30-45 and withdrawn when eGFR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.
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.
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.
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
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.