Prescriber 2011 22(19), 5th October

Two useful articles about diabetes.

Antidiabetic drugs in renal dysfunction

Metformin: Confusing because the summary of product characteristics advise it shouldn’t be used below 60 ml/min creatinine clearance, but NICE advises using it until creatinine clearance drops below 30 ml/min and most clinicians would go along with that.  This article advises weighing up the risks and benefits once the eGFR goes below 45.  The reason for not using it in renal failure is the risk of lactic acidosis, but this is very rare (1:10 000).  Whatever cut-off you use, do note that if someone’s only dropped below it due to intercurrent illness it should be restarted when the eGFR recovers.  Oh, and also notice that obesity causes the eGFR to be underestimated by the standard equation.

Sulphonylureas: Higher risk of hypoglycaemia with renal failure.  Glipazide is a good one to use in this case as it isn’t cleared by the kidneys.  Consider making sure they can self-monitor for hypoglycaemia, especially if they drive.

Glitazones: Can be used down to an eGFR of 4ml/min, but have their other disadvantages in terms of SEs/risks.

Gliptins: Experience of using these in patients with moderate/severe CKD is limited.  Only one licenced for use is saxagliptin, and only at a dose of 2.5 mg daily, with monitoring of renal function.  It is not recommended for use in dialysis patients.  All that said, one of the physicians on the Expert Panel Discussion said it would be his preferred choice of second-line therapy in a patient with an eGFR of 40, due to the SEs of sulphonylureas & glitazones.

GLP-1 analogues: Exenatide can be used in moderate renal impairment (eGFR 30 – 45 ml/min) with care – best to keep 5 mg bd as maximum.  Liraglutide is not recommended below 60 ml/min due to lack of clinical trial experience, although pharmacokinetic/pharmacodynamic studies show no significant accumulation down to eGFR 15.

Insulin: About a third of the dose gets metabolised by the kidney.  One of the members of the expert panel advised lowering the dose by 25% for patients in stage 3 or lower; another said the dose ‘might need to be reduced quite significantly’ in patients with eGFR <30 ml/min.


Incretin effect

This is more of a helpful bit of background science explaining how the GLP-1 analogues (exenatide, liraglutide) and DPP-4 inhibitors (gliptins) work.  The insulin response on eating a certain amount of glucose is, in non-diabetics, considerably larger than that caused by infusing the same amount of glucose IV.  This is called the incretin effect, and is caused by the gut itself secreting substances called incretins, of which the main one is GLP-1 (glucagon-like peptide).  These have a number of effects which only really work in the presence of hyperglycaemia, which mean that drugs based on this effect are unlikely to cause hypoglycaemia.  Useful, hey?  The effects include an increased feeling of satiety, which is why these drugs are helpful for promoting weight loss.

Physiological incretins have a very short half-life due to being rapidly broken down by dipeptidyl peptidase-4, more snappily known as DPP-4.  This gives pharmacologists two avenues of research – longer-lasting GLP analogues, and DPP-4 inhibitors.  So there you go – two more that I understand more about.


About Dr Sarah

I'm a GP with a husband and two young children.
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