Evidence-base - International Diabetes Federation

Outcomes studies compared with other agents are limited [9] but both the UKPDS
[12] and ADVANCE study [13] showed that intensive therapy with sulfonylureabased
treatment improved long-term outcomes. The ADVANCE study achieved
this without weight gain and with low rates of hypoglycaemia [13] .
a-glucosidase inhibitors are widely used and are popular in many, especially
Asian, countries [14] . Gastrointestinal side effects such as flatulence and
diarrhoea are frequent. Hanefeld et al performed a meta-analysis on the effect
of the a-glucosidase inhibitor acarbose on cardiovascular events in seven
randomized placebo-controlled studies of at least 52 weeks duration and found
significantly reduced risk for myocardial infarction and any cardiovascular
event [15] .
When monotherapy fails to achieve target glycaemia, a second agent is
required. Of the many options, the addition of a sulfonylurea is recommended
as the usual approach for people on metformin. Alternatives include addition
of an α-glucosidase inhibitor, DPP-4 inhibitor or thiazolidinedione. There is
little to choose between options based on efficacy alone. Combination therapy
decreases HbA 1c levels more than monotherapy by about 1% point / 11mmol/
mol, with most combinations providing similar reductions [9] . Therefore choices
are driven by availability, cost and untoward effects and combined metformin
and sulfonylurea therapy remains widely used throughout the world. Probably
because of this, few studies have specifically examined long-term outcomes
with this combination.
Other options as second-line therapy should be considered if the use of either
metformin or sulfonylurea is associated with side effects or contraindicated.
An α-glucosidase inhibitor is effective in combination with metformin or
sulfonylurea and is an option in countries where it is commonly prescribed.
DPP-4 inhibitors act to increase levels of endogenous incretin hormones. A
meta-analysis by Amori et al [16] reported that compared with placebo DPP-4
inhibitors lowered HbA 1c by approximately 0.7% / 8 mmol/mol and were weight
neutral. DPP-4 inhibitors have proven efficacy when combined with metformin,
sulfonylurea or both metformin and sulfonylurea. There are a lack of studies
evaluating long-term efficacy and safety but a number of outcome studies are
currently underway. These agents are relatively expensive in many countries.
Thiazolidinedione (peroxisome proliferator-activated receptor-g agonist)
effectively lower blood glucose when used as monotherapy, dual or triple
therapy. However their side effects and increasing safety concerns have
seen their use decrease. The most common adverse effects are weight gain
and fluid retention which may result in peripheral oedema and congestive
heart failure. Increasingly recognised is the increased incidence of fractures,
especially in females [17] . Some meta-analyses suggest an increased risk of
myocardial infarction with rosiglitazone [18,19] , although this was not apparent
in the RECORD study [20] . Pioglitazone has not been associated with an increase
in cardiovascular risk and the PROactive study reported some improved
outcomes [21] . However recent concerns have been raised about a possible link
with bladder cancer when used for more than a year. Although thiazolidinediones
are included as an option in the IDF algorithm, other choices are favoured and
the situation with respect to safety continues to be monitored by IDF, especially
with respect to any further regulatory restrictions.
If diabetes control remains unsatisfactory and a third agent is required, the
usual approach options include either adding a third oral agent or commencing
insulin. Options for a third oral agent include a DPP-4 inhibitor, an α-glucosidase
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