174
VOLUME 8 NUMBER 4 • NOVEMBER 2011
JOURNAL UPDATE
SA JOURNAL OF DIABETES & VASCULAR DISEASE
rioration of glycaemic control. Such second-
ary treatment failure necessitates escalation
of drug doses or the use of a combination
of drugs with complementary mechanisms
of action to maintain glycaemic control over
time. Current treatment guidelines indicate
that patients with inadequate glycaemic con-
trol may benefit from the addition of a third
oral antidiabetic drug before initiating insulin
therapy.
Dipeptidylpeptidase-4 (DPP-4) inhibitors
inhibit the degradation of incretin hormones,
glucagon-like peptide-1 and glucose-de-
pendent insulinotropic polypeptide, thereby
increasing insulin secretion and decreasing
glucagon secretion after meals. These drugs
may also improve
β
-cell function. Given the
distinct but complementary mechanisms of
action of alogliptin (DPP-4 inhibitor), met-
formin and pioglitazone, triple oral therapy
with these drugs has the potential to address
both insulin resistance and Islet dysfunction.
South Africa’s Helderberg Diabetes and Med-
ical Centre has made a contribution to the
study of efficacy and safety of triple oral ther-
apy in the diabetic patient with inadequate
glycaemic control.
The aim of this study was to assess the
efficacy and safety of adding alogliptin 25
mg (triple oral therapy) versus uptitrating
pioglitazone from 30 to 45 mg for 52 weeks
in type 2 diabetes patients with inadequate
glycaemic control on metformin (≥ 1 500 mg
or maximum tolerated dose) and pioglita-
zone 30 mg.
Triple oral therapy in patients with inad-
equate glycaemic control provided clinically
relevant and superior improvemnt in A
1c
com-
pared with uptitrating pioglitazone, without
increasing safety or tolerability concerns.
The glycaemic benefits of triple therapy
were seen as early as week four and main-
tained throughout the 52-week period. Clini-
cally relevant improvements were observed
regardless of age, gender, ethnicity, race and
baseline BMI.
Key take-home message:
Adding aloglip-
tin to an existing metformin–pioglitazone
regimen provides superior glycaemic control
and potentially improves
β
-cell function with
no clinically important differences in safety,
compared to uptitrating pioglitazone.
Source: Bosi E, Ellis GC,
et al.
Alogliptin as a third
oral antidiabetic drug in patients with type 2 diabetes
and inadequate glycemic control on metformin and
pioglitazone: a 52-week, randomized, double-blind,
active-controlled, parallel-group study.
Diabetes,
Obesity Metabol
2011; (in press). DOI: 10.1111/j.1463-
1326.2011.01463.x.
Ultra-long-acting insulin degludec
provides comparable glycaemic con-
trol to daily insulin glargine without
additional adverse events
Despite the availability of many therapies,
many people with diabetes are unable to
reach guideline-recommended rates of
glycosylated haemoglobin (HbA
1c
). Insulin
degludec is an ultra-long-acting basal insu-
lin analogue in clinical development. Phar-
macokinetic properties of insulin degludec
result in an ultra-long-action profile, making
possible new applications of alternate-day
or three-times weekly injection of this insu-
lin. This can potentially help with accept-
ance and early initiation of insulin therapy
for some people with type 2 diabetes.
This clinical proof-of-concept trial aimed
to assess the efficacy and safety of insulin
degludec once a day or three times a week,
compared with insulin glargine once a day in
combination with metformin. The study sub-
jects were insulin-naïve type 2 diabetics who
were inadequately controlled on oral anti-
diabetic drugs. Participants were randomly
allocated to receive (1) insulin degludec (900
nmol/ml) three times a week, or (2) insulin
degludec (600 nmol/ml or 900 nmol/ml) once
a day, or (3) insulin glargine (600 nmol/ml) once
a day; all in combination with metformin.
Insulin degludec provided once a day or
three times a week as add-on to metformin
did not differ from insulin glargine in terms
of glycaemic control. There were no appar-
ent treatment-specific patterns or clustering
of adverse events.
Source: Zinman B, Fulcher G,
et al
. Insulin degludec, an
ultra-long-acting basal insulin, once a day or three times
a week versus insulin glargine once a day in patients with
type 2 diabetes: a 16-week, randomised, open-label,
phase 2 trial.
Lancet
2011;
377
: 924–931. DOI: 10.1016/
S0140-6736(10)62305-7.
Benefits of fibrates in reducing
cardiovascular events for type 2
diabetic patients questioned
Lowering the concentration of LDL choles-
terol with statins substantially reduces the
rate of cardiovascular events among patients
with underlying CVD or other risk factors.
Yet a substantial risk persists, suggesting that
additional lipid-modifying interventions may
be needed.
High TG levels and low levels of HDL
cholesterol independently correlate with
increased cardiovascular risk. There remains
considerable controversy over the clinical
efficacy of fibrates in overall cardiovascular
benefit. Fenofibrate has been approved for
use in reducing LDL cholesterol, TG, total cho-
lesterol and apolipoprotein B levels; as well as
increasing HDL cholesterol levels in patients
with primary hypercholesterolaemia or mixed
dyslipidaemia. Fenofibric acid (the active
ingredient of fenofibrate) is the only fibrate
approved for use with a statin for reducing
TG levels and raising HDL cholesterol levels
in patients with mixed dyslipidaemia and cor-
onary heart disease or those who have equiva-
lent risk levels and are receiving optimal statin
therapy. To date, there is no data on direct
clinical outcomes to support this indication.
The ACCORD-Lipid substudywas designed
to determine whether combination therapy
with a statin plus fenofibrate would reduce
the risk of cardiovascular events, compared
with statin monotherapy. After a follow-up
of almost five years, fenofibrate plus simvas-
tatin had not significantly decreased the rate
of the primary outcome of fatal cardiovascu-
lar events, non-fatal myocardial infarction or
non-fatal stroke, compared with simvasta-
tin alone. However, a sub-group analysis of
patients with baseline TG levels above 204
mg/dl and HDL cholesterol levels below 34
mg/dl showed a 31% reduction in the rate of
primary outcome.
The question of the appropriate way to
handle the approved indication for fenofi-
bric acid for co-administration with a statin
is controversial. The ambiguity for physicians
who must make individualised decisions for
patients needs to be removed. It is suggested
that until sufficient evidence emerges, physi-
cians prescribing combination statin–fibrate
therapy should selectively target high-risk
patients only after optimal control of LDL
cholesterol has been achieved with statin
therapy.
A properly designed trial is warranted to
test the hypothesis that adding fenofibric
acid to statin therapy significantly reduces
the risk of cardiovascular events among high-
risk patients who have reached their LDL cho-
lesterol goal with a statin but have residual
mixed dyslipidaemia.
Key take-home message:
Fenofibrates
work to lower cardiovascular risk in patients
with TG levels raised above 2.3 mmol/l and
HDL cholesterol levels below 1.0 mmol/l.
Other type 2 diabetes patients do not show
benefit from fenofibrate addition.
Source: Goldfine AB, Kaul S,
et al.
Fibrates in the
treatment of dyslipidemias – time for a reassessment.
New Engl J Med
2011;
365
(6): 481–484.
Glenda Hardy