VOLUME 11 NUMBER 2 • JUNE 2014
67
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
meta-analysis of randomised clinical trials to evaluate the
cardiovascular safety of SUs. They concluded that ‘in type 2 diabetes,
the use of sulfonylureas is associated with increased mortality and a
higher risk of stroke, whereas the overall incidence of major adverse
cardiovascular events (MACE) appears to be unaffected.’
Given the inconsistency of the literature with regard to SUs
and cardiovascular outcomes, a SU cardiovascular outcome trial is
required to clarify the effect of SUs on cardiovascular outcomes.
16,17
Dose–response relationships
The literature supports the use of SUs at doses lower than the
maximum manufacturer’s recommended dose.
18
Studies have
shown that as the dose of SU is increased, there is initially a direct
relationship between dose and blood glucose-lowering effect.
18
However, further dose increase results in no further reduction in
blood glucose levels, and, when the dose is further increased, the
glycaemic profile actually worsens.
18
Modified-release formulations have further reduced the
SU dose that is required, compared to the immediate-release
pharmaceutical preparation.
19
For example gliclazide is available in
a modified-release formulation that uses less than half of the dose
of the immediate-release formulation.
19
Cost considerations
SUs remain affordable. This is relevant in countries that have
limited resources and competing healthcare problems. In sub-
Saharan Africa, there are epidemics of not just metabolic and
cardiovascular disease, but also infectious diseases.
20
Tuberculosis
and parasitic diseases such as malaria remain major healthcare
challenges, while diabetes, hypertension and traumatic injuries
are increasing.
21
Therefore scarce medical resources must be
distributed to various disease-management programmes.
However, one may argue that managing SU-induced
hypoglycaemic events (the cost of treating and in some cases the
cost of admission), raises their cost. One may mitigate this added
cost by using the newer SUs that have fewer propensities to cause
hypoglycaemia compared to older agents.
Newer classes of anti-diabetic agents
The ideal anti-diabetic drug should be safe, efficacious and cost
effective. It should not only reduce HbA
1c
levels but also reduce
macro- and microvascular complications. Furthermore, it must not
cause weight gain and hypoglycaemia, and must have durable
efficacy and long- term safety. There is continuing research to
develop newer agents to emulate the characteristics of an ideal
anti-diabetic agent, and therefore better manage type 2 diabetes
patients.
Sodium glucose co-transport (SGLT) inhibitors and incretin-based
therapies are new classes of anti-diabetic agents. SGLT inhibitors
reduce weight and have fewer propensities to cause hypoglycaemic
events.
22
This is in contrast to the SU class that increases weight
and the number of hypoglycaemic episodes.
Incretin-based therapies include glucagon-like peptide (GLP)
analogues and di-peptidyl dipeptidase IV (DPPIV) inhibitors. GLP
analogues reduce weight but are administered via the parenteral
route. DPPIV inhibitors are weight neutral, have a low propensity
for hypoglycaemia and are administered orally.
The uncertainty surrounding adverse cardiovascular events
associated with therapy with SUs remains,
15
in contrast to the DPPIV
class, which has both meta-analysis
23
and a cardiovascular outcome
trial
24
that demonstrate cardiovascular safety of this new class.
There are safety concerns with newer anti-diabetic agents.
For example, issues related to pancreatitis and pancreatic cancer
remain with incretin-based therapies.
25
However, the American
Diabetes Association (ADA), European Association for the Study
of Diabetes (EASD) and the International Diabetes Federation
(IDF) have issued a joint statement saying that there is inadequate
information presently to demonstrate a causal relationship
between incretin-based therapy and pancreatitis and pancreatic
cancer.
26
There are also concerns with the SGLT inhibitor class and
bladder and breast malignancies, and urinary and genital tract
infections.
22
The newer agents require further phase IV data to
inform clinical use.
Maximising benefits and minimising adverse effects
of SUs
After considering the adverse effects, safety concerns, efficacy data
and cost, one must use SUs in a manner that maximises efficacy
while limiting the potential for adverse effects. The question is
how does the clinician do this? One way is to choose the ‘right
sulphonylurea, at the right dose, for the right patient’.
The right sulphonyureas:
The SUs share a common mode of
action. However, there are differences in pharmacokinetics and
pharmacodynamics between individual SUs. Some SUs have fewer
propensities for hypoglycaemia and weight gain than others.
27
South African treatment guidelines for type 2 diabetes
specifically mention that glibenclamide must be phased out, and in
the interim it must be dispensed only if renal function is known.
28
Data derived from the UK General Practice Research Database (719
general practitioner practices, 34 052 patient-years of SU therapy)
reported that in users of SUs, the annual risk of any hypoglycaemic
event was 1.8%, rising to 2.0% in those aged > 65 years. The risk
of SUs was greatest for glibenclamide; the study reported 25%
fewer recorded episodes for gliclazide and 40% fewer for glipizide
compared with glibenclamide.
29
At the right dose:
Given the data on dose-response relationships
of the class, it is prudent to use the lowest effective dose of SU,
guided by efficacy parameters such as HbA
1c
levels .
For the right patient:
SUs are more likely to cause adverse
effects in patients with risk factors for hypoglycaemia, including
older, frail patients and patients with clinically significant renal
impairment.
30
In addition, any hypoglycaemic effect may be
devastating for specific patients, such as bus drivers. Therefore SUs
should perhaps be avoided in these groups and newer anti-
diabetic drugs considered.
Conclusion
Cost issues remain a barrier between the newer anti-diabetic drugs
and the majority of South African type 2 diabetes patients. SUs,
if used at the right dose (the lowest possible effective dose), for
the right patient (in younger patients without renal impairment),
remain an option for the management of type 2 diabetes patients
in resource-constrained settings.
References
1.
McGill JB. Pharmacotherapy in type 2 diabetes: a functional schema for drug
classification.
Curr Diabetes Rev
2012;
8
(4): 257–267.
2.
Mazzola N. Review of current and emerging therapies in type 2 diabetes mellitus.
Am J Manag Care
2012;
18
(1 Suppl): S17–26.
