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cumulation in renal disease, in theory, could cause the same phenom-
enon. However, even in those with CKD, lactic acidosis is a very rare
event. 21, 22 While stopping metformin in patients with CKD would elimi-
nate this risk, it seems more prudent to reduce metformin dosing by one
third in patients with eGFR between 30-45 ml/min/1.73m . In some pa-
2 3
tients with stable renal impairment and an eGFR of 15-30 ml/min/1.73m
2
metformin can also be safely used, at approximately half the normal
dose. However, caution should be exercised in patients with unstable
renal function, and those with co-morbid heart failure, alcoholism or
liver disease, and the drug should be stopped 2–3 days prior to surgery
or any procedure using iodinated radiographic contrast media, as a
sudden decline in renal function can lead to drug accumulation in a
hypoxic setting where lactate production may be already increased. 3

The effects of kidney function on counter-regulatory
response to hypoglycaemia

Falling blood glucose levels trigger the activation of a range of coun-
ter-regulatory responses, that contribute to both the symptomatology
of the event as well as its reversal. The key regulators of this response
23
include increased secretion of glucagon, growth hormone and cortisol
as well as adrenergic activation. Each of these may be substantially
abnormal in patients with advanced diabetes, and especially those
with CKD. The effects of autonomic nervous system dysfunction asso-
24
ciated with advanced diabetes on catecholamine release in response
to hypoglycaemia are well known, contributing to both defective glu-
cose counter-regulation and hypoglycaemia unawareness. Many pa-
tients also take sympathetic blocking medications, which impair counter-
regulatory glycogenolysis by the liver, although the risk is lower with
selective beta-blockers than non-selective agents. Even in the ab-
25
sence of autonomic neuropathy, many patients with type 2 diabetes
show attenuated glucagon, growth hormone, and cortisol responses
to hypoglycaemia. In particular, insulin-dependent patients with type
2 diabetes, who represent the majority of those with advanced CKD,
have extremely impaired glucagon response to hypoglycaemia when
compared to controls and those with type 2 diabetes treated with oral
hypoglycaemics, reflecting the more advanced pancreatic damage
observed in these patients. In addition, elevated insulin concentrations
in CKD, due to impaired renal clearance, inhibit glucagon release in
response to low blood glucose. Rather than prevent hypoglycaemia,
growth hormone and cortisol are “slow-acting” hormones that act to
limit its severity and duration. Again, both these pathways are abnor-
mal in patients with CKD, with dysfunction correlating with the severity
of renal impairment.

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