VOLUME 11 NUMBER 2 • JUNE 2014
69
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
Correspondence to: Intekhab Ahmed
Thomas Jefferson University and Hospitals, Philadelphia, PA, USA
Tel: 215-955-5752;
Fax: 215-928-3160
e-mail:
Melinda Ukrainski, Lindsay Ann Bischoff
Thomas Jefferson University Hospital, Philadelphia, PA, USA
Tatiana Gandrabura
Atlanticare Regional Medical Center, Atlantic City, NJ, USA
Originally published in
Int J Diabetol Vasc Dis Res
2013;
1
: 301
.
S Afr J Diabetes Vasc Dis
2014;
11
(2): 69–72
On the horizon: new oral therapies for type 2 diabetes
mellitus
MELINDA UKRAINSKI, TATIANA GANDRABURA , LINDSAY ANN BISCHOFF, INTEKHAB AHMED
Abstract
The first documented case of diabetes mellitus occurred
earlier than 4000 BC. Since then, many of the brightest
minds in medicine have dedicated their time and effort
toward developing treatments that can reverse the
course of this deadly disease. As our understanding of the
pathogenesis of diabetes increases, so does the availability
of treatment options. The fight against diabetes once only
had metformin and sulfonylureas as the cornerstone of oral
treatment, but now, multiple classes have been added to this
armamentarium including thiazolidenediones (TZDs) and
dipeptidyl peptidase IV (DDP IV) inhibitors. These therapies
provide reasonable durable glycemic control but are unable
to arrest the natural progression of diabetes or the eventual
need for insulin. By utilizing our growing knowledge on
the pathogenesis of diabetes, a number of new therapeutic
agents are in development to overcome the shortcomings of
current therapies. Promising options on the horizon include
sodium-coupled glucose co-transport 2 (SGLT2) inhibitors,
ranolazine, salicylates, second-generation peroxisome
proliferator-activator receptor agonists (PPARs), and 11-beta
hydroxysteroid dehydrogenase type 1 inhibitors (11-beta
HSD1 inhibitors). Various molecules, including some enzymes,
are also in development, particularly to address beta-cell
preservation and its sensitivity to glucose, while minimising
hypoglycaemia. Most of these new classes of drugs consist
of daily administration, simplifying the regimen for patients
and likely increasing medication compliance.
This article reviews the new agents that are advancing
through clinical trials, their mechanism of actions, glucose
lowering effect and possible side effects and limitations.
Keywords:
type 2 diabetes, SGLT2 inhibitors, ranolazine,
salicylates, second-generation Ppars, 11
β
-HSD1 inhibitors,
glucokinase activators, fructose 1,6-bisphosphatase inhibitors
Introduction
Diabetes mellitus afflicts approximately 400 million people
worldwide and, without any significant change in this trend, by
2030 more than 552 million people will be diabetic.
1
Our current
treatment options are able to maintain reasonable glycaemic control
for a period of time; however, they are unable to stop the pro-
gression of disease leading to deteriorating glycaemic control over
time and subsequent need for increasingly complicated treatment
regimens.
The two core defects of type 2 diabetes mellitus (T2DM) are
insulin resistance and pancreatic beta-cell dysfunction or failure.
2
Insulin resistance appears to be the first and main defect, resulting
in an increased demand of insulin release from beta-cells to
normalise glucose levels. Overtime, the the beta-cells’ ability to
maintain this level of hyperinsulinemia deteriorates resulting in
the hyperglycaemia characteristic of T2DM. Insulin resistance
is attributed to ectopic lipid deposition in the liver and skeletal
muscle, and changes in adipose tissue, resulting in inflamed tissue
leading to the release of a multitude of inflammatory cytokines
and decreased release of favorauble cytokines and hormones.
3,4
By
the time a person develops diabetes, 50–80% of insulin secretory
function of the beta-cells is lost.
4
Additional factors influencing
beta-cell dysfunction include aging, genetic factors and biochemical
abnormalities such as lipotoxicity, glucotoxicity, inflammation,
amyloid deposition, and reactive oxygen species.
5
Current therapies for T2DM are based on targeting these two
core defects. Metformin and sufonylureas (SUs) are by far the
most commonly prescribed medications for T2DM management.
Unfortunately, they are unable to arrest the natural course of
decline in beta-cell function, their effects are not long lasting,
6
and
they each carry their own side-effect profile, with hypoglycaemia of
particular concern with SU use. Thiazolidinediones (TZDs) improve
insulin sensitivity but are notorious for their side effects, such as
fluid retention, weight gain, fracture, and potential risk of bladder
cancer.
7,8
Members of the incretin family include DPP-IV inhibitors
and glucagon-like peptide (GLP-1) analogs and each have their
own limitations. The former have a limited effect on A
1c
reduction
and a potentially increased risk of pancreatitis, while the latter are
injectable and also carry the risk of pancreatitis.
9,10
New therapies, while continuing to address the same two
core defects, are being designed to also target various molecular
pathways involved in the pathogenesis of T2DM, normalise
hyperglycaemia, and minimise the complications of T2DM.
Sodium-coupled glucose co-transporter 2 inhibitors
(SGLT2 inhibitors)
The kidneys play a significant role in maintaining glucose
homeostasis via the filtration and reabsorption of glucose. The
reabsorption of glucose predominantly occurs on the brush border
membrane of the convoluted segment of the proximal tubule.
Glucose enters the tubular cells by a sodium-dependent active
carrier-mediated transport process and exits via the basolateral
