Mechanism of Action and Cardiovascular/Renal Effects of SGLT2 Inhibitors

This essay discusses the mechanism of action of SGLT2 inhibitors, a class of drugs used to reduce blood glucose levels in adults with type 2 diabetes. It elaborates on their role in improving cardiovascular and renal outcomes, including reducing the risk of mortality and myocardial infarction or ischemic stroke, lowering blood pressure, and providing renal protection. The inhibitors prevent the reabsorption of glucose in the kidney, leading to glucosuria and subsequent excretion of sugar in urine. The essay also highlights the effects of dapagliflozin, empagliflozin, and other gliflozin drugs on glycaemic control, body weight, blood pressure, HDL cholesterol levels, and renal function.

Running head: DRUG MECHANISM
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1DRUG MECHANISM
Introduction- The sodium glucose co-transporter 2, commonly referred to as SGLT2 is a
protein encoded in humans by the SLC5A2 gene. It is a member of the family of sodium glucose
co-transporter that is sodium dependent transport proteins facilitating movement of glucose. The
primary role of the co-transporter is associated with reabsorption of glucose in the kidney.
Sodium glucose co-transporter 2 inhibitors also referred to as gliflozin, belong to a medication
class that are involved in inhibition glucose reabsorption, thereby reducing the blood sugar
levels. These drugs primarily inhibit the SGLT2 that are specifically used for the treatment of
type 2 diabetes (1). Apart from controlling the glycaemic index, gliflozins have also been found
functional in bringing about significant cardiovascular benefits to all patients, diagnosed with
T2D (2). This essay will discuss the mechanism of action of the group of drugs and will also
elaborate on their role on cardiovascular and renal functioning.
Mechanism of action- SGLT2 is principally expressed on the epithelial cell linings of the
kidneys (specifically the proximal convoluted tubule) and is accountable for an estimated 90% of
the glucose reabsorption in the kidneys. In other words, sodium glucose co-transporter 2
inhibitors prevent the reuptake of glucose in the kidney from the glomerular filtrate, and thereby
result in lowering the glucose levels in the blood stream. This in turn promotes the subsequent
excretion of sugar or glucose in urine, in the form of glucosuria. Dapagliflozin is a highly
selective and competitive inhibitor of SGLT2. The activities of the inhibitors are controlled by
the kidney function, and underlie glucose control of the patient who is being administered the
drug (3). The effects of glucosuria also increase with a rise in the circulating blood sugar level.
With an excretion of high glucose levels, the plasma levels in the patient drastically fall, thereby
leading to an enhancement in the overall glycaemic parameters.

2DRUG MECHANISM
In other words, the mechanism of action of these inhibitors is largely dependent on the
blood sugar level, and contrasting action of thiazolidinediones, the popular oral antidiabetic
drugs, the former are not dependent on the actions of the insulin hormone (4). Therefore, there is
minimum potential for the onset of hypoglycaemia among the patients, thus reducing risks of
beta cell overstimulation. Considering the fact that the mechanism of action principally depends
on normal function of the renal cells, efficacy of the inhibitors are often reduced among person
with complete renal impairment.
Cardiovascular effect- A study that investigated the effects of this inheritance on the
cardiovascular outcomes of patients suffering from end stage renal disease and T2D found that
use of the inhibitor was associated with a significant 57% and 24% reduced risk of mortality and
myocardial infarction or ischemic stroke, among patients who underwent chronic dialysis.
Furthermore, use of the inhibitors was also not significantly associated with an elevation in the
susceptibility to heart failure among ESRD patients (5). Administration of empagliflozin was
allied with a noteworthy decrease in risks related to cardiovascular death, when associated to
patients who were subjected to placebo treatment (6). The inhibitors have been found to lower
the blood pressure by promoting process of intravascular volume contraction and osmotic
diuresis. Intravascular volume reduction stimulates the RAAS system and activates the type 1
angiotensin receptors.
Owing to the fact that glycosuria results in excess of loss of water into the urine, with
subsequent dehydration, the drug is directly responsible for onset of osmotic diuresis. Lower
rates of adverse cardiac events observed in another study with patients were randomised to a
group that received empagliflozin (7). The role of the SGLT2 inhibitors in improving
cardiovascular outcomes can be related to their impacts in decreasing the overall levels of

3DRUG MECHANISM
HbA1C, maintaining body weight, reducing blood pressure, and increasing the levels of HDL
cholesterol in blood (8). Similar findings have also been presented in another study that
elaborated on the fact that empagliflozin is responsible for lowering the composite primary
cardiovascular end point, in T2D patients (9).
Renal effect- The class of inhibitors is also responsible for providing renal protection and
preventing onset of diabetic neuropathy, among diabetics. Upon increasing the reabsorption of
sugar and sodium from the proximal convoluted tubule (PCT), the sodium delivery gets
decreased to the juxtaglomerular apparatus. This is followed by an increase in production of
angiotensin and renin. This results in contraction of the efferent arteriole and relaxation of the
afferent arteriole. The inhibitors increase distribution of sodium to the juxtaglomerular apparatus,
help in vasoconstriction of the efferent arteriole, and reduce interglobular pressure, thereby
providing renal protection (10). In patients having reduced GFR, the amount of glucose that
reaches the proximal convoluted tubule decreases. Further effects of SCLT2 inhibitors are
related to a decrease in urine albumin, reduced progression to the condition microalbuminuria,
improved albuminiuria, and an overall reduction in worsening of renal impairment condition
(11).
A study that investigated the impacts of dapagliflozin therapy on the kidney morphology
and renal protection among T2D patients also found that the treatment significantly resulted in an
improvement in glycaemic control and enhanced UACR, which in turn was related to a
substantial decreasing mass of body fat, among the diabetes patients (12). The inhibitors are also
responsible for improving the length of the kidney, radiation attenuation and enhancement of
proximal fibula injury marker. Improvement in renal threshold related to glucose excretion is
another significant effect of the inhibitors (10). Further evidences also suggest that empagliflozin

4DRUG MECHANISM
is related to alterations in renal and myocardial metabolism, from fat oxidation to ketone body
that consequently leads to an improvement in renal function and efficiency (6).
Conclusion- Thus, it can be concluded that sodium glucose co-transporter 2 inhibitors are
a class of prescribed medications approved by the FDA, for usage with exercise and diet, in order
to reduce blood glucose levels in adults suffering from type 2 diabetes. These inhibitors usually
block the action of SGLT2 proteins that prevents reabsorption of glucose by the kidney, and help
in removal of excess blood sugar from the body, in the form of urine. Besides lowering the level
of sugar in the bloodstream, the drug is also responsible for improving the cardiovascular and
renal outcomes.

5DRUG MECHANISM
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