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Diabetes Management SGLT2 Inhibitors
The Importance of Reducing Hyperglycemia While Preserving Insulin Secretion—
The Rationale for Sodium-coupled Glucose Co-transporter 2 Inhibition in Diabetes
Serge A Jabbour, MD, FACP, FACE
Associate Professor of Medicine, and Interim Director, Division of Endocrinology, Diabetes, and Metabolic Diseases,
Jefferson Medical College, Thomas Jefferson University
Abstract
The prevalence of type 2 diabetes continues to rise in a number of countries, presenting a need for additional effective therapeutic options to
be developed. This condition has often been treated with medications that can lead to hypoglycemia (sulfonylureas), weight gain
(thiazolidinediones), or other side effects, including the gastrointestinal side effects sometimes experienced with metformin. Sodium-coupled
glucose co-transporter 2 (SGLT2) inhibitors are a novel class of drugs under investigation that target the kidney’s ability to reabsorb glucose into
the bloodstream, improving glycemic control and aiding weight loss without inducing hypoglycemia. These compounds have shown
encouraging results in several studies without any serious adverse events. They could therefore potentially become an important addition to
the currently available diabetes treatments.
Keywords
Sodium-coupled glucose co-transporter 2 (SGLT2) inhibitor, hyperglycemia, glucose reabsorption, type 2 diabetes, glucosuria, dapagliflozin,
sergliflozin, remogliflozin, phlorizin, proximal tubule
Disclosure: Serge A Jabbour, MD, FACP, FACE, is on the speaker’s bureau for Amylin and Eli Lilly.
Received: November 23, 2009 Accepted: December 16, 2009
Correspondence: Serge A Jabbour, MD, FACP, FACE, Associate Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolic Diseases, Jefferson Medical College of
Thomas Jefferson University, 211 South Ninth Street, Ste 600, Philadelphia, PA 19107. E: Serge.Jabbour@jefferson.edu
Type 2 diabetes affects an individual’s ability to correctly regulate Glucose and the Kidneys
plasma glucose levels in the body, potentially leading to serious The normal physiology of glucose regulation involves a delicate balance
adverse events, including cardiovascular disease.
1,2
It is characterized in the functions of different organ systems to maintain a plasma
by insulin resistance and beta-cell dysfunction with resultant glucose level of 80–110mg/dl.
10
Despite large fluctuations that occur
hyperglycemia.
3
This condition affects more than 300 million people due to glucose intake in the form of meals and elimination from
worldwide
4
and close to 24 million people in the US.
5
Obesity and physical exertion, glucose concentrations in the blood are kept within
weight gain have been reported to be leading risk factors for type 2 this narrow range.
11
Mechanisms such as insulin production in the
diabetes.
6,7
With obesity continuing to escalate in industrialized pancreas, glucose uptake by the brain and peripheral tissues, and
countries, the prevalence of diabetes is likely to increase substantially gluconeogenesis in the liver and, to a lesser extent, the kidneys
in the coming years. In fact, the incidence of type 2 diabetes in the US contribute to controlling glucose levels.
has been projected to reach 36.2 million people by 2025, an increase
of 57% from 2003.
8
The kidney contains approximately 1.3 million nephrons, with each
consisting of a glomerulus and a long tubule made up of three
Various therapies have become established in the treatment of this components: the proximal tubule, the loop of Henle, and the distal tubule.
12
potentially fatal disease, although finding optimal treatment options In addition to gluconeogenesis, a major additional function of the kidneys
remains a challenge. Traditionally, strategies to counter hyperglycemia is to reabsorb the approximately 180g of glucose that filters through the
have involved developing medications that enhance insulin secretion glomeruli every day (see Figure 1).
13
In individuals without diabetes and
and/or improve insulin sensitivity,
9
in particular metformin, sulfonylureas, with normal renal function, virtually all of the glucose that passes through
and thiazolidinediones. Recently, dipeptidyl peptidase 4 (DPP-4) inhibitors the kidneys is reabsorbed into the bloodstream; this is essential for energy
and glucagon-like peptide 1 (GLP-1) mimetics have been added to this conservation. This reabsorption is mediated by the sodium-coupled
list. However, new drugs are constantly being developed and a novel glucose co-transporters 1 and 2 (SGLT1 and SGLT2, respectively) located on
class of agents currently under investigation focuses on a different the proximal tubule. SGLT2 is a high-capacity, low-affinity transporter
strategy altogether, working to reduce hyperglycemia through the expressed in the S1 segment of the proximal tubule and is responsible for
inhibition of glucose reabsorption in the kidneys. 90% of renal glucose reabsorption.
14
The remaining 10% is reabsorbed
© TOUCH BRIEFINGS 2009 75
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