The papers in this month’s digest are loosely connected by exploring current prescribing practice in people with diabetes and chronic kidney disease (CKD). Clemens and colleagues describe the changing use of oral hypoglycaemic agents (OHAs) in an elderly (>65 years) population with CKD in Canada between 2004 and 2013. They found that metformin was used in 27.6% of people with an estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2.
The message that shorter-acting sulfonylureas (SUs) should not be used in this population seems to have been received, but 9.5% of the cohort were still prescribed glibenclamide in 2013, including 11.4% of those on dialysis. Although gliclazide is relatively short-acting and mostly metabolised in the liver, current guidance in the British National Formulary recommends avoidance in people with severe renal impairment. Safer alternatives such as gliptins are also being prescribed, but it should be remembered that these too can cause hypoglycaemia when taken with SUs, and their dose should be reduced as GFR falls.
Hippisley-Cox et al analysed the GP research database over an 8-year period up to 2015 and matched recorded serious clinical outcomes in 275000 individuals aged 25–84 years who received OHAs. They found an increased incidence of severe kidney failure with gliptin or glitazone use, and a reduced incidence with metformin. On the other hand, triple therapy was associated with less blindness compared to metformin monotherapy. These findings are, on the face of it, contradictory in terms of the relationship of metformin to microvascular complications in the kidney and eye. However, the results are almost certainly confounded by indication; metformin is contraindicated in people with renal impairment, so prescribing rates should have been lower in this population.
People with visual impairment may struggle with multiple therapies, and treatments with a low risk of hypoglycaemia, such as metformin, are likely to be preferred for safety reasons. It would also be incorrect to presume that all visual and renal impairment in this population is diabetes-related. The most common cause of visual loss in the elderly is age-related macular degeneration, and loss of GFR is most often a result of nephrosclerosis. As in the Clemens study, significant numbers of people with advanced CKD were prescribed metformin and SUs. Higher rates of hypoglycaemia were also observed with multiple OHA regimens that included SUs.
Wong et al report the long-term follow-up of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) study, suggesting that people in the intensive glycaemic control arm (based upon modified-release gliclazide) had reduced rates of end-stage renal disease (requiring dialysis or transplantation) or renal death 5.4 years after the study ended. However, there were few events, the indications for dialysis were not standardised and the effect size was greater for people with relatively preserved renal function and lower blood pressure, which requires explanation.
Finally, Muller et al evaluated OHA prescriptions in 301 people with type 2 diabetes referred to nephrology services in four centres in France, and found that 53.5% were using agents or dosages outside recommendations. It made no difference whether the referring doctor was a GP, diabetologist or nephrologist.
What can we conclude from all this? Firstly, we are poor at following prescribing guidance and should do better. The advice on metformin use has been revised in the US and is now in line with that in Europe: caution should be exercised and the dose reduced in people with GFR <45 mL/min/1.73 m2, and metformin should be avoided in those with GFR <30 mL/min/1.73 m2 (US Food and Drug Administration, 2016). Secondly, hypoglycaemia is a risk for all those with CKD who are taking SUs; this risk increases as GFR declines and is significant for all SUs and insulin, and for those on multiple therapies. Finally, we need to be wary of associative studies (which can never prove causation) and long-term follow-up of clinical trial cohorts (which can never fully substantiate efficacy). I am not sure that these papers make a murky area any clearer, but they should at least prompt more careful prescribing in this vulnerable population with CKD and diabetes.
To read the article summaries, please download the PDF