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The effect of kidney function on sulphonylurea (SU)
antidiabetics

Sulphonylurea (SU) agents are widely used in the management of pa-
tients with type 2 diabetes, to directly stimulate the release of insulin
from the beta cells of the pancreas. Hypoglycaemia is the most com-
mon complication of SU agents, occurring when insulin stimulation is
not matched with food intake in those with irregular eating habits or
medication compliance. Some SU agents are directly eliminated by
the kidneys, or are metabolised in the liver to a variety of active com-
pounds, which are then excreted by the kidneys. As a result, first gener-
ation sulphonylurea drugs, including tolazamide, acetohexamide and
chlorpropamide , and glibenclamide (glyburide), a second-generation
19
sulphonylurea with an active metabolite , are more likely to cause
20
hypoglycaemia in individuals with renal impairment, and should not
be used in this setting. By contrast, SU drugs with inactive metabolites
including tolbutamide, glipizide, gliclazide and gliquidone are less likely
to cause hypoglycaemia, although, as noted above, in patients with
CKD, the half-life of endogenous insulin is prolonged. Consequently,
SU-induced hypoglycaemia is also more common in those with im-
paired kidney function, regardless of the SU agent or formulation. All
SUs should be used cautiously and with a dose reduction in patients
with a reduced eGFR. 3

Kidney Function and Metformin

One largely unheralded reason for an increased incidence of hypo-
glycaemia in diabetic patients with CKD, is the fact that the most widely
used oral anti-diabetic agent, metformin, is often stopped and re-
placed with agents including insulin and secretagogues that are more
likely to induce hypoglycaemia, weight gain and other side effects.
By contrast, hypoglycaemia is generally not observed with metformin
used as monotherapy, which acts as an insulin sensitiser to lower glu-
cose levels by reducing hepatic production of glucose and slowing
the absorption of glucose from a meal. The rationale for stopping met-
formin and substituting drugs with a potentially worse side effect pro-
file is problematic. 21, 22 Certainly, the excretion of biguanides such as
metformin and phenformin is largely dependent on renal clearance,
by both glomerular ultrafiltration and tubular secretion. Consequent-
ly, in patients with renal impairment, plasma concentrations may be
significantly elevated and the drug may accumulate. This accumula-
tion of phenformin has been associated with an increased risk of lactic
acidosis, although data regarding the risk associated with metformin in
CKD are less clear and largely anecdotal. When taken in an overdose,
metformin can cause lactic acidosis, implying that significant drug ac-

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