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3. T2DM therapy in patients at risk of and
with declining renal function

Professor Paola Fioretto
University of Padova
Department of Medical and Surgical Sciences
Padova, Italy

Chronic kidney disease and the T2DM patient

As we have seen in Chapter 2, declining kidney function is a significant
problem in T2DM (affecting as much as 40% of patients , not only with
1
regard to the long-term prognosis for the person with this condition, but
also because of the implications for the therapeutic management of
hyperglycaemia, the root cause, via different pathogenetic pathways,
of diabetic chronic complications.

As an example of how renal impairment impacts T2DM management,
we only need to look at the incidence of hypoglycaemia among T2DM
patients who also have some degree of chronic kidney disease (CKD).
These patients are at a 240% higher risk of hypoglycaemia compared
with those patients with normal renal function. That is a huge differ-
2
ence and one that undoubtedly changes the attitudes of the patients
towards their medication and makes clinicians think twice before pre-
scribing certain anti-diabetic agents. The main reason for this huge in-
crease in the risk of hypoglycaemia is the fact that the kidneys play
a pivotal role in the clearance and degradation of insulin, as well as
several oral agents.

The kidney clears insulin via two distinct routes. The first route entails
glomerular filtration, while the second involves diffusion from the peri-
tubular capillaries. With renal clearance impaired, the half-life of insulin
3
is prolonged via a number of mechanisms and there is a concomitant
decrease in the insulin requirement of the T2DM patient. This relation-
3
ship between kidney function and the clearance of insulin means that
hypoglycaemia in T2DM patients with CKD is a particular hazard where
any compounds that stimulate the production of insulin are being used;
notably the secretagogues (see below). For example, around 74% of
sulphonylurea (SU) -induced severe hypoglycaemic events occur in
patients with declining renal function. 4

Regardless of these risks, the recent Kidney Disease Outcome Qual-
ity Initiative (KDOQI) clinical practice guidelines and clinical practice
recommendations for diabetes and chronic kidney disease maintain
that target HbA levels should be <7% irrespective of the presence or
1c
absence of CKD. The rationale for this seemingly strict guidance is that
hyperglycaemia is the fundamental cause of vascular organ compli-
cations, including kidney disease. Furthermore, intensive treatment of
5
hyperglycaemia is the most effective approach to prevent diabetic
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