SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that modulate
sodium-glucose transport proteins
Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter, SGLT) are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron ( SGLT2 ...
in the
nephron
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
(the functional units of the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
), unlike
SGLT1 inhibitors that perform a similar function in the
intestinal mucosa
The gastrointestinal wall of the gastrointestinal tract is made up of four layers of specialised tissue. From the inner cavity of the gut (the lumen) outwards, these are:
# Mucosa
# Submucosa
# Muscular layer
# Serosa or adventitia
The mucosa is ...
. The foremost metabolic effect of this is to inhibit
reabsorption of glucose in the kidney and therefore lower
blood sugar
Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...
.
They act by inhibiting
sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of
type II diabetes mellitus
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
(T2DM). Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in patients with
type II diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
(T2DM).
Several medications of this class have been approved or are currently under development. In studies on
canagliflozin
Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is a third-line medication to be tried after metformin, a first-line medication for type 2 diabetes. It is used together with ex ...
, a member of this class, the medication was found to enhance blood sugar control as well as reduce
body weight
Human body weight is a person's mass or weight.
Strictly speaking, body weight is the measurement of weight without items located on the person. Practically though, body weight may be measured with clothes on, but without shoes or heavy accessor ...
and systolic and diastolic
blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
.
Medical uses
The 2022
ADA
Ada may refer to:
Places
Africa
* Ada Foah, a town in Ghana
* Ada (Ghana parliament constituency)
* Ada, Osun, a town in Nigeria
Asia
* Ada, Urmia, a village in West Azerbaijan Province, Iran
* Ada, Karaman, a village in Karaman Province, ...
standards of medical care in diabetes include SGLT2 inhibitors as a first line pharmacological therapy for type 2 diabetes (usually together with metformin), specifically in patients with
chronic kidney disease
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
,
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
or
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
.
A
systematic review
A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
and
network meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
comparing SGLT-2 inhibitors,
GLP-1 agonists, and
DPP-4 inhibitors
Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.
The first agent of the class – sita ...
demonstrated that use of SGLT2 inhibitors was associated with a 20% reduction in death compared with placebo or no treatment. Another systematic review discussed the mechanisms by which SGLT-2 inhibitors improve cardio-renal function in patients with type 2 diabetes mellitus, emphasizing the impacts in improving neural tone.
Two reviews have concluded that SGLT2 inhibitors benefit patients with atherosclerotic
major adverse cardiovascular events Major adverse cardiovascular events (MACE, or major adverse cardiac events) is a composite endpoint frequently used in cardiovascular research. Despite widespread use of the term in clinical trials, the definitions of MACE can differ, which makes ...
(MACE).
One of those studies defined MACE as the composite of
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
,
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
, or cardiovascular death.
Adverse effects
Genital infections seem to be the most common
adverse effect
An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...
of gliflozins. In
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s
fungal infections
Fungal infection, also known as mycosis, is disease caused by fungi. Different types are traditionally divided according to the part of the body affected; superficial, subcutaneous, and systemic. Superficial fungal infections include common ti ...
,
urinary tract infection
A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...
s and
osmotic diuresis
Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pro ...
were higher in patients treated with gliflozins.
In May 2015, the
FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
issued a warning that gliflozins can increase risk of
diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of ...
(DKA).
By reducing glucose blood circulation, gliflozins cause less stimulation of endogenous
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
secretion or lower dose of exogenous insulin that results in diabetic ketoacidosis. They can specifically cause ''euglycemic'' DKA (euDKA, DKA where the blood sugar is not elevated) because of the renal tubular absorption of ketone bodies. A particularly high risk period for ketoacidosis is the perioperative period. SGLT2 inhibitors may need to be discontinued before surgery, and only recommended when someone is not unwell, is adequately hydrated and able to consume a regular diet.
In September 2015, the FDA issued a warning related to canagliflozin (Invokana) and canagliflozin/metformin (Invokamet) due to decreased bone mineral density and therefore increased risk of bone fractures. Using gliflozins in combination therapy with metformin can lower the risk of
hypoglycemia
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
compared to other T2DM such as sulfonylureas and insulin.
[
Increased risk of lower limb amputation is associated with canagliflozin but further data is needed to confirm this risk associated with different gliflozins. A ]European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
review concluded that there is a potential increased risk of lower limb amputation (mostly affecting the toes) in people taking canagliflozin, dapagliflozin and empagliflozin.
In August 2018, the FDA issued a warning of an increased risk of Fournier gangrene
Fournier gangrene is a type of necrotizing fasciitis or gangrene affecting the external genitalia or perineum. It commonly occurs in older men, but it
can also occur in women and children. It is more likely to occur in diabetics, alcoholics, or th ...
in patients using SGLT2 inhibitors. The absolute risk is considered very low.
To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA has approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery.[ ]
Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.
In the FDA Adverse Event Reporting System
The FDA Adverse Event Reporting System (FAERS or AERS) is a computerized information database designed to support the U.S. Food and Drug Administration's (FDA) postmarketing safety surveillance program for all approved drug and therapeutic biol ...
an increase was reported in events of acute kidney injury
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI are cla ...
associated with SGLT2 inhibitors, though data from clinical trials actually showed a reduction in such events with SGLT-2 treatment.
Interactions
Interactions are important for SGLT2 inhibitors because most T2DM patients are taking many other medications. Gliflozins appear to increase the diuretic effect of thiazides
Thiazide () refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first ...
, loop diuretics
Loop diuretics are diuretics that act on the Na-K-Cl cotransporter along the thick ascending limb of the loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or c ...
and related diuretics
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
and may increase the risk of dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
and hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
. It is important to adjust the dose of antidiabetics if the treatment is combination therapy to avoid hypoglycemia. For example, interactions with sulfonylureas have led to severe hypoglycemia presumably due to cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
.
A study has shown that it is safe to consume dapagliflozin along with pioglitazone
Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not re ...
, metformin, glimepiride
Glimepiride, is an anti-diabetic medication used to treat type 2 diabetes. It is less preferred than metformin. Use is recommended together with diet and exercise. It is taken by mouth. Glimepiride takes up to three hours for maximum effect and l ...
, or sitagliptin
Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. It is taken by mouth. It is also a ...
and dose adjustment is unnecessary for either medication. It is unlikely that food intake has clinical meaningful impact on the efficacy of dapagliflozin, therefore it can be administered without regard to meals.
Members
These are the known members of the gliflozin class:
* Canagliflozin
Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is a third-line medication to be tried after metformin, a first-line medication for type 2 diabetes. It is used together with ex ...
was the first SGLT2 inhibitor to be approved for use in the United States. It was approved in March 2013, under the brand name Invokana and it was also marketed throughout the EU under the same name.
* Dapagliflozin
Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease.
Common side effects include hy ...
is the first SGLT2 inhibitor approved anywhere in the world by the EU in 2012. It was approved for use in the United States under the brand name Farxiga by the Food and Drug Administration in January 2014. the first oral treatment in combination with insulin to treat type 1 diabetes mellitus in UK and EU.
* Empagliflozin
Empagliflozin, sold under the brand name Jardiance among others, is an antidiabetic medication used to improve glucose control in people with type2 diabetes, to reduce the risk of cardiovascular death in adults with type2 diabetes and establis ...
, approved in the United States in August 2014, under the brand name Jardiance by Boehringer Ingelheim
C.H. Boehringer Sohn AG & Co. is the parent company of the Boehringer Ingelheim group, which was founded in 1885 by Albert Boehringer in Ingelheim am Rhein, Germany. As of 2018, Boehringer Ingelheim is one of the world's largest pharmaceutical ...
. Of the gliflozins, empagliflozin and tofogliflozin have the highest specificity for SGLT2 inhibition.[ This oral medicine for type 2 diabetes has been shown to reduce the risk of cardiovascular death.
* Ertugliflozin was approved in the United States under the brand name Steglatro in December 2017.
* Ipragliflozin, produced by the Japanese company ]Astellas Pharma
is a Japanese multinational pharmaceutical company, formed on 1 April 2005 from the merger of and . On February 5, 2020, the company announced management changes effective from April 1, 2020.
Astellas is a member of the Mitsubishi UFJ Fina ...
Inc. under the brand name Suglat, approved in Japan January 2014.
* Luseogliflozin
Luseogliflozin (trade name Lusefi) is a pharmaceutical drug (an SGLT2 inhibitor) used for the treatment of type 2 diabetes mellitus. It was approved for use in Japan in 2014.
In a meta-analysis involving data from 10 randomized controlled trials ...
was approved in Japan March 2014 under the brand name Lusefi and was developed by Taisho Pharmaceutical.
* Remogliflozin etabonate
Remogliflozin etabonate (INN/USAN) is a drug of the gliflozin class for the treatment of non-alcoholic steatohepatitis ("NASH") and type 2 diabetes. Remogliflozin was discovered by the Japanese company Kissei Pharmaceutical and is currently being ...
was commercially launched first in India by Glenmark in May 2019.
* Sergliflozin etabonate discontinued after Phase II trials.
* Sotagliflozin is a dual SGLT1/SGLT2 inhibitor in phase III trials under the brand name Zynquista. Developed by Lexicon pharmaceuticals. It was planned to be the first oral treatment in combination with insulin to treat type 1 diabetes mellitus. The Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
refused its approval for use in combination with insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
for the treatment of type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...
.
* Tofogliflozin was approved in Japan in March 2014, under the brand names Apleway and Deberza developed by Sanofi
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
and Kowa Pharmaceutical.
Mechanism of action
Sodium Glucose cotransporters (SGLTs) are proteins that occur primarily in the kidneys and play an important role in maintaining glucose balance in the blood. SGLT1 and SGLT2 are the two most known SGLTs of this family. SGLT2 is the major transport protein and promotes reabsorption
In renal physiology, reabsorption or tubular reabsorption is the process by which the nephron removes water and solutes from the tubular fluid (pre-urine) and returns them to the circulating blood. It is called ''reabsorption'' (and not ''absorpt ...
from the glomerular filtration
Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pre ...
glucose back into circulation and is responsible for approximately 90% of the kidney's glucose reabsorption.[ SGLT2 is mainly expressed in the kidneys on the ]epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
lining the first segment of the proximal convoluted tubule. By inhibiting SGLT2, gliflozins prevent the kidneys' reuptake of glucose from the glomerular filtrate and subsequently lower the glucose level in the blood and promote the excretion of glucose in the urine (glucosuria
Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused ...
).
The mechanism of action on a cellular level is not well understood. Work is underway to define this mechanism as a prodiuretic with great promise. However, it has been shown that binding of different sugars to the glucose site affects the orientation of the aglycone An aglycone (aglycon or genin) is the compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid molecule.
Detection
A way to identify aglycone ...
in the access vestibule. So when the aglycone binds it affects the entire inhibitor. Together these mechanisms lead to a synergistic interaction. Therefore, variations in the structure of both the sugar and the aglycone are crucial for the pharmacophore of SGLT inhibitors.
Dapagliflozin is an example of an SGLT-2 inhibitor, it is a competitive, highly selective inhibitor of SGLT. It acts via selective and potent inhibition of SGLT-2, and its activity is based on each patient's underlying blood sugar control and kidney function
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's fluid ...
. The results are decreased kidney reabsorption of glucose, glucosuria effect increases with higher level of glucose in the blood circulation. Therefore, dapagliflozin reduces the blood glucose concentration with a mechanism that is independent of insulin secretion and sensitivity, unlike many other antidiabetic medications. Functional pancreatic β-cells are not necessary for the activity of the medication so it is convenient for patients with diminished β-cell function.
Sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
and glucose are co-transported by the SGLT-2 protein into the tubular epithelial cells across the brush-border membrane of the proximal convoluted tubule
The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. It can be further classified into the proximal convoluted tubule (PCT) and the proximal straig ...
. This happens because of the sodium gradient between the tubule and the cell and therefore provides a secondary active transport of glucose. Glucose is later reabsorbed by passive transfer of endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
into the interstitial glucose transporter protein.
Ratios of activity between SGLT1 and SGLT2 may be helpful in defining expression.
Pharmacology
The elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
, bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
, protein binding
Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...
, the blood concentration Cmax
CMAX is a bus rapid transit (BRT) service in Central Ohio, operated by the Central Ohio Transit Authority (COTA). The line begins in Downtown Columbus, traveling northeast to Westerville. CMAX is Central Ohio's first bus rapid transit line; it ...
at time tmax, and other pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
parameters of various medications of this class are present in table 2. These medications are excreted in the urine as inactive metabolites.
*''Cmax:'' Maximum serum concentration that drug achieves in body after the drug has been and administrated
*''tmax:'' Time to achieve maximum plasma concentration
*''t1/2:'' Biological half-life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
In studies that were made on healthy people and people with type II diabetes mellitus, who were given dapagliflozin in either single ascending dose (SAD) or multiple ascending dose (MAD) showed results that confirmed a pharmacokinetic profile of the medication. With dose-dependent concentrations the half-life is about 12–13 hours, Tmax 1–2 hours and it is protein-bound, so the medication has a rapid absorption and minimal excretion by the kidney.
Dapagliflozin disposition is not evidently affected by BMI or body weight
Human body weight is a person's mass or weight.
Strictly speaking, body weight is the measurement of weight without items located on the person. Practically though, body weight may be measured with clothes on, but without shoes or heavy accessor ...
, therefore the pharmacokinetic findings are expected to be applicable to patients with a higher BMI. Dapagliflozin resulted in dose-dependent increases excretions in urinary glucose, up to 47g/d following single-dose administration, which can be expected from its mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
, dapagliflozin.
In some long term clinical studies that have been made on dapagliflozin, dapagliflozin was associated with a decrease in body weight which was statistically superior compared to placebo or other active comparators. It is primarily associated with caloric rather than fluid loss.
In contrast with other anti-hyperglycemic diabetes medication
Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists (liraglutide, exenatide, and others), and pramlintide, all are administered orally and are thu ...
s, SGLT2 inhibitors enhance, rather than suppress, gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
and ketogenesis
Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under ...
. Because SGLT2 inhibitors activate sirtuin 1
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.
SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (''S. cerevisiae''), referring to the fact t ...
(and thus PGC-1α
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the ''PPARGC1A'' gene. PPARGC1A is also known as human accelerated region 20 ( HAR20). It may, therefore, have played a key ro ...
and FGF21
Fibroblast growth factor 21 is a liver-secreted peptide hormone that in humans is encoded by the ''FGF21'' gene. Together with FGF19 (FGF15 in rodents) and FGF23, this protein is a member of the endocrine subgroup within the fibroblast growth fa ...
), they are more cardioprotective than the other medications used to treat diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
.
Structure-activity relationship
The structure-activity relationship (SAR) of gliflozins is not fully understood.
The most common gliflozins are dapagliflozin, empagliflozin and canagliflozin. The differences in the structures is relatively small. The general structure includes a glucose sugar with an aromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
group in the β-position at the anomeric
In carbohydrate chemistry, a pair of anomers () is a pair of near-identical stereoisomers that differ at only the anomeric carbon, the carbon that bears the aldehyde or ketone functional group in the sugar's open-chain form. However, in order for ...
carbon. In addition to the glucose sugar moiety and the β-isomeric aryl substituent the aryl group is composed of a diarylmethylene structure.
The synthesis of Gliflozins involves three general steps. The first one is the construction of the aryl substituent, the next one is the introduction of the aryl moiety onto the sugar or glucosylation of the aryl substituent and the last one the deprotection and modification of the arylated anomeric center of the sugar.
Phlorizin was the first type of gliflozin and it was non-selective against SGLT2/SGLT1. It is a natural O-aryl glycoside composed of a d-glucose and an aromatic ketone. However Phlorizin is very unstable, it is rapidly degraded by glucosidases in the small intestines, so it can not be used as an oral administration medication to treat diabetes. Structural modifications have been made to overcome this instability problem. The most efficient way was to conjugate aryl moiety with glucose moiety since C-glucosides are more stable in the small intestines than O-glucoside derivatives (C-C bond instead of C-O-C bond).
In the sugar analogues of dapagliflozin, the β-C series are more active than α-C series so it is critical that the β-configuration is at C-1 for the inhibitory activity. Both dapagliflozin and empagliflozin contain a chlorine
Chlorine is a chemical element with the Symbol (chemistry), symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate betwee ...
(Cl) atom in their chemical structure. Cl is a halogen
The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In the modern IUPAC nomenclature, this group is ...
and it has a high electronegativity
Electronegativity, symbolized as , is the tendency for an atom of a given chemical element to attract shared electrons (or electron density) when forming a chemical bond. An atom's electronegativity is affected by both its atomic number and the d ...
. This electronegativity withdraws electrons off the bonds and therefore it reduces the metabolism. The Cl atom also reduces the IC50 value of the medication so the medication has better activity. The carbon-fluorine bond (C-F) has also has a veryl low electron density
In quantum chemistry, electron density or electronic density is the measure of the probability of an electron being present at an infinitesimal element of space surrounding any given point. It is a scalar quantity depending upon three spatial va ...
.
For example, in the chemical structure of canagliflozin a fluorine atom is connected to an aromatic ring then the compound is more stable and the metabolism of the compound is reduced.
Empagliflozin contains a tetrahydrofuran ring but not canagliflozin nor dapagliflozin.
In the development of gliflozins the distal ring contains a thiophene ring instead of an aromatic ring. However the final chemical structures of the marketing gliflozins does not contain this thiophene ring.
Alternative pharmacological actions
SGLT2 inhibitors increase circulating ketone
In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
body concentrations. The cardioprotective effects of SGLT2 inhibitors have been attributed to the elevated ketone levels.
Gliflozins have been posited to exhibit protective effects on the heart, liver, kidneys, anti‐hyperlipidemic, anti‐atherosclerotic
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no sy ...
, anti‐obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
, anti‐ neoplastic effects in ''in vitro'', pre‐clinical, and clinical studies. Pleiotropic effects of this class have been attributed to a variety of its pharmacodynamic actions such as natriuresis, hemoconcentration, deactivation of renin-angiotensin-aldosterone system, ketone body formation, alterations in energy homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
, glycosuria
Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused ...
, lipolysis
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important ...
, anti‐inflammatory, and antioxidative actions.
History
Phlorizin is a molecule with SGLT inhibiting properties, and served an important role in the development of the gliflozin class of medications.
References
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Anti-diabetic drugs
ca:Gliflozina