70
VOLUME 11 NUMBER 2 • JUNE 2014
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
membrane by facilitated diffusion utilising a sodium-independent
glucose transporter (GLUTs).
11
The sodium-dependent glucose
co-transporters are a family of glucose transporters found in the
intestinal mucosa of the small intestine (SGLT1) and the proximal
tubule of the nephron (SGLT2, predominantly, and SGLT1).
12
SGLT1
and SGLT2 are members of the SLC5A gene family (also known as
the sodium substrate symporter gene family. Twelve of these have
been identified in the human genome, and several of these
(including SGLT1 and SGLT2) are associated with sodium glucose
transport. These transporters use the electrochemical sodium
gradient generated by the Na
+
/K
+
-ATPase is the driving force for
the symporter activity. SGLT2 is the principal transporter and is
responsible for 90% of glucose reabsorption in the kidney. SGLT2
is expressed in the S1 segment of the proximal tubule while SGLT1
is expressed in the S3 segment of proximal tubule and estimated to
account for 10% of glucose reabsorption.
11,12
Sodium-coupled glucose co-transporter 2 inhibitors are a class
of agents initially derived from phlorizin, a natural component of
apple tree bark, that blocks glucose reabsorption in the proximal
tubule of the kidney.
13
T2DM patients have increased activity of SGLT2 resulting in
increased glucose reabsorption
14
and, therefore, its inhibition is
a logical site for intervention. Several oral SGLT2 inhibitors are
in different phases of clinical trial. Canagliflozin, dapaglifozin,
ipraglifozin, topoglifozin and empaglifozin are the most studied
drugs in this class. The FDA recently approved Canagliflozin, with
the requirement that five post-marketing studies be done including:
a study to examine cardiovascular outcomes, a pharmacovigilance
programto report the incidences ofmalignancies, severepancreatitis,
liver abnormalities, adverse events during pregnancy; a study to
evaluate bone safety, and two paediatric studies.
15
Dapaglifozin
is approved for use in the European Union but its approval is
delayed in the USA due to concerns about an imbalance in breast
and bladder cancer events with more cases developing in patients
taking the drug.
16
The drop in haemoglobin A
1c
(HbA
1c
) with most
of these drugs is in the range of 0.7–0.96% with modest weight
loss, which is dose dependent, and ranges from 1.35 kg with small
dose and 2 kg with maximum tolerable doses.
17
Some side effects
of these agents include hypoglycaemia, urinary tract infections,
genital mycotic infections, salt and volume depletion, and other
electrolyte losses such as calcium and magnesium.
16,17
It has not
been approved for patients with significant renal impairment and
those requiring haemodialysis. If further data on safety and efficacy
continue to be reassuring, SGLT2 inhibitors have a promising future
in the management of diabetes.
Ranolazine
Ranolazine, an anti-anginal medication with proven cardiovascular
safety profile, acts by inhibiting late sodium current in cardiac
tissue.
18
Its mechanism of action for glucose lowering is unknown,
but may include augmentation of glucose-induced insulin release
and a beta-cell protective effect.
20
A
post hoc
analysis of a study
using ranolazine in T2DM patients revealed that the participants on
ranolazine had a lower HbA
1c
level. The placebo-adjusted drop in
HbA
1c
level after four months of treatment was 0.42–0.59%.
Another notable finding was that the patients on ranolazine did
not have a significant difference in hypoglycaemic episodes when
compared to placebo, and also did not change the incidence of
hypoglycaemic episodes in patients already on anti-hyperglycaemic
therapies, including sulfonylureas.
19,20
Salicylate derivatives
The use of salicylates for the treatment of diabetes was proposed
over 100 years ago based on the observation that diabetic patients
taking salicylates showed improvement in their blood sugar levels.
21
Our understanding of T2DM as a result of a chronic inflammatory
state has re-invigorated the interest in salicylates as a therapeutic
option for T2DM. The proposed mechanism of action is via inhibition
of NF-kB, which increases the production of pro-inflammatory
cytokines, promoting insulin resistance and down-regulating the
insulin-sensitising adiponectin.
21,22
Some studies have reported
evidence that salicylates also directly inhibit adipocyte lipolysis,
resulting in decreased FFA levels and increased insulin sensitivity.
Multiple small clinical trials have been done to evaluate the effect
of salicylates on T2DM. Most of these are limited by small sample size
and length of study. They also required very high doses of salicylates
to achieve the effect, and these were associated with numerous
side effects, particularly gastrointestinal bleeding, tinnitus, and
hearing loss.
23
Salsalate, a non-acetylated salicylate, is a promising
new therapy for T2DM. Salsalate does not affect the COX enzymes,
making it a much safer and tolerable option at higher doses than
aspirin and other acetylated salicylates. One study examining the
benefit of salsalate in T2DM revealed a significant dose-dependent
drop in HbA1c levels of up to 0.49% with 4g of salsalate. Potential
concerns include mild increases in microalbumin-to-creatinine ratio
and in LDL cholesterol levels.
23-25
Peroxisome proliferator activator receptor agonists
(PPARs)
The PPARs are a group of nuclear receptors known as ligand-
inducible transcription factors, which play diverse roles in regulating
growth and metabolism. There are three major isotypes, PPAR-
α
,
-
γ
and -
δ
. They form heterodimers with retinoid X receptors (RXR)
to either stimulate or repress gene transcription. PPAR-
α
is mainly
expressed in liver, heart and kidney, and plays a role in fatty acid
oxidation and lipoprotein metabolism. PPAR-
γ
is expressed in
adipose tissue, macrophages, and osteoblasts. It is involved in
adipose tissue differentiation and triglyceride synthesis. PPAR-
δ
is
expressed in skeletal muscle, cardiac muscle, and adipose tissue,
where it stimulates fat oxidation.
26
It also is expressed in liver
and immune cells where it has a role in reducing hepatic glucose
production and inflammation, respectively.
TZDs are an example of PPAR-
β
agonists, and have had a major
impact on reducing insulin resistance to date. Unfortunately, their
use has dramatically decreased due to their potential untoward side
effects.
The first TZD, troglitazone, was associated with liver toxicity;
rosiglitazone showed increased cardiovascular morbidity, and
pioglitazone is linked with a potentially increased risk of bladder
cancer and osteoporosis.8 These side effects appear to be secondary
to the non-selectivity of these molecules. Because of their impressive
effectiveness in T2DM, there is an ongoing effort to the develop
second generation of PPAR agonists with more selective action and
fewer side effects.
Balaglitazone, a newer partial PPAR-y agonist, has been
suggested to be as efficacious in lowering blood glucose with less
adverse systemic effects.
24,25
In the BALLET trial, Henriksen
et al
.
compared the effects of balaglitazone to pioglitazone. After 26
weeks, 10 mg of balaglitazone lowered HbA
1c
levels by 0.99%,
compared to –1.11% for 20 mg balaglitazone, and –1.22% for
