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Limitations of current therapies

The central aim of T2DM management is to maintain near to normal
blood glucose levels accomplished via a daily regimen of diet, exer-
cise and antidiabetic agents or insulin injections, without exposing the
patients to the risk of hypoglycaemia and weight gain. Unfortunately,
the very nature of the disease and the strict, daily regimen for its man-
agement are a perfect recipe for very poor compliance.
Oral antidiabetic agents (OADs) are a cornerstone of T2DM treatment;
however, these compounds fail to provide sustainable and sufficient
glycaemic control. Large, long-term trials, such as UKPDS and ADOPT
have demonstrated that the glycaemic lowering effect of T2DM treat-
ments decreases with time. 42 43 The UKPDS trial demonstrated that af-
ter three years of monotherapy with OADs, 50% of patients were ad-
equately controlled. However, after nine years of monotherapy only a
quarter of patients still maintained adequate glycaemic control. 43

The underlying reason for OADs being unable to provide sustainable
glycaemic control is a declining glycaemic response, which in turn is a
consequence of differences in genotypes interacting with external en-
vironmental factors to produce an in-vivo milieu that varies from person
to person thus influencing the effects of a medication. The differences
44
between people with T2DM, both physiologic and genetic and how a
greater understanding of these factors can lead to individualised treat-
ments for patients are discussed in more detail in Chapter 5. For the
purposes of this chapter and the limitations of current treatments, the
variables that influence the individual response to OAD are as follows: 45

z Duration of diabetes.
z Baseline HbA (reflecting the severity of the disease).
1c
z Anti-diabetes treatment status (treatment naive vs. treatment non-naive).
z The hyperglycaemic treatment strategy (initiation or combination therapy
vs. up-titration of existing therapy).

A further limitation of current therapies is their ability to treat T2DM peo-
ple with co-morbidities, most notably chronic kidney disease. As part
of the overarching metabolic syndrome, T2DM and kidney disease are
intimately linked and the progression of the latter is definitely depend-
ent on how the former is managed. As we have seen, many of the
widely used OADs are a very blunt instrument when it comes to man-
aging blood glucose levels in T2DM patients with concomitant kidney
disease. Many of these compounds are excreted renally and kidney
disease potentiates their activity resulting in a variety of complications.

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