66
VOLUME 11 NUMBER 2 • JUNE 2014
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Optimal utilisation of sulphonylureas in resource-
constrained settings
POOBALAN NAIDOO, VIRENDRA RAMBIRITCH, NEIL BUTKOW, SELVARAJAH SAMAN
Abstract
Sulphonylureas (SUs) are oral anti-diabetic drugs (OADs)
that were introduced more than 60 years ago. Clinicians are
familiar with their use and they remain extensively used.
However, the SU class is associated with adverse effects of
weight gain and hypoglycaemia. In addition, their effects on
cardiovascular events remain contentious. Newer classes of
anti-diabetic agents have been developed and these agents
are weight neutral (di-peptidyl peptidase IV inhibitors), while
others reduce weight (glucagon-like peptide analogues and
sodium glucose co-transporter inhibitors). Furthermore, the
newer agents are less likely to cause hypoglycaemia and have
a potentially better cardiovascular safety profile. However,
the newer agents are more costly than SUs and their long-
term safety is unknown. It is therefore likely that SUs will
continue to be used, and more so in resource-limited settings.
One may mitigate the adverse effects of weight gain and
hypoglycaemia associated with the SU class by using members
within this class that are less probable to cause these adverse
effects. Furthermore, the specific SU must be used at the
lowest effective therapeutic dose. In patients at high risk of
SU-induced hypoglycaemic episodes (frail, clinically significant
renal impairment), or patients in whom hypoglycaemic
episodes may have devastating effects (bus drivers), newer
anti-diabetic agents may be a justifiable alternative option.
Keywords:
type 2 diabetes mellitus, sulphonylureas, resource-
constrained settings
Introduction
Sulphonylureas (SUs) were developed in the 1950s.
1
They reduce
blood glucose levels by increasing insulin secretion from the
pancreatic beta-cells. At the cellular level SUs block potasssium (K
ATP
)
channels and increase calcium influx, which results in the release of
insulin from the vesicles.
1
Correspondence to: Dr Poobalan Naidoo
Boehringer Ingelheim, Johannesburg
e-mail:
Virendra Rambiritch
University of Kwa-Zulu Natal, Durban
Neil Butkow
University of Witwatersrand, Johannesburg
Selvarajah Saman
Port Shepstone Regional Hospital and University of Kwa-Zulu Natal, Durban
Originally published in
Cardiovascular J Afr
2014;
25
(2): 88.
S Afr J Diabetes Vasc Dis
2014;
11
(1): 66–68
Currently there is an expansion in the therapeutic armamentarium
of agents for type 2 diabetes. The therapeutic landscape is complex
and comprises pharmacologically distinct molecules, including
biguanides, sulphonylureas, incretin-based therapies and renal
sodium glucose co-transporter (SGLT) inhibitors.
2
As novel therapies
are inevitably associated with increased costs, this article focuses
on ways to utilise SUs in a manner that maximises efficacy and
concurrently minimises adverse effects.
Efficacy and durability of glycaemic effect
Type 2 diabetes patients benefit from intensive multifactorial risk-
factor modification.
3
In addition to control of blood glucose and
glycosylated haemoglobin (HbA
1c
) levels, lifestyle modification (diet
and exercise), and control of blood pressure and cholesterol levels
are crucial to reduce the risk of cardiovascular disease in type 2
diabetes patients.
3
For blood glucose control, HbA
1c
level is the most robust endpoint
used in clinical trials to evaluate the efficacy of anti-diabetic drugs.
HbA
1c
is an indicator of three-month average blood glucose levels.
Reduction in HbA
1c
levels reduces microvascular complications.
4-6
SUs reduce HbA
1c
levels by approximately 1.5%,
2
but their
effect on cardiovascular outcomes is contentious. Their HbA
1c
level-reducing ability is adequate but durability is limited.
7
Limited
durability is probably secondary to type 2 diabetes mellitus being
a progressive disease characterised by gradual reduction in beta-
cell mass and function. If there are limited numbers of beta-cells,
then the action of this class is limited because the mode of action
necessitates the presence of beta-cells; they cannot increase insulin
secretion if there are no beta-cells present to synthesise and release
insulin.
Furthermore, secondary failure has also been attributed to
the detrimental effects of SUs on residual pancreatic beta-cells.
8
Secondary failure rates were found to be lowest with gliclazide (7%),
compared with glibenclamide (17.9%) and glipizide (25.6%).
9
Safety data
SUs cause weight gain
2,10
and significantly increase the risk of
hypoglycaemia.
11,12
Hypoglycaemia appears to be associated with
adverse vascular events and death.
13
There are also issues with regard to cardiovascular safety. There
is inconsistency in the results of clinical studies in respect of SUs
and cardiovascular safety. The University Group Diabetes Program
14
demonstrated increased cardiovascular mortality in patients treated
with tolbutamide. However, the United Kingdom Prospective
Diabetes Study (UKPDS)
4
and the ADVANCE Collaborative Group
5
did not show an association between treatment with an SU and
adverse cardiovascular outcomes.
In a meta-analysis of 33 studies, with more than a million study
subjects, SU use was associated with a significantly increased risk
of cardiovascular death (relative risk 1.27, 95% confidence interval
1.18–1.34,
n
= 27 comparisons).
15
Monami
et al
.
16
conducted a
