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An Overview on Anti Diabetic Drugs and Development

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DOI: 10.22232/stj.2016.04.02.05

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 Science and Technology Journal, Vol. 4 Issue: II ISSN: 2321-3388

An Overview on Anti Diabetic Drugs and

Development
Ved Prakash Singh
Department of Chemistry, School of Physical Sciences,
Mizoram University, Aizawl–796004, Mizoram, India
E-mail: [email protected]

Abstract—Diabetes mellitus is one of the world’s major diseases and is the third leading cause of death in the United
States after heart disease and cancer. In the India, about 2–6% population suffer from diabetes or related complication.
Anti-diabetic drugs treat diabetes mellitus by lowering glucose levels in the blood. Mostly anti-diabetic drugs are
administered orally except the insulin, exenatide, and pramlintide. There are different types of anti-diabetic drugs, and
their selection depends on the nature of the diabetes, age and situation of the person, and many other factors. Treatments
include the agents which increase the amount of insulin secreted by the pancreas, or increase the sensitivity of target
organs to insulin, and agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract. People
are mainly focused on insulin, insulin analogues, oral hypoglycemic agents and various other complementary and alternate
medicines to control the blood glucose levels in diabetes. The present review summarizes in brief about the drugs used for
treatment of diabetes mellitus.

Keywords: Diabetes Mellitus, Glucose, Antidiabetic Drugs, PPAR, Insulin

INTRODUCTION • Genetic defects in insulin action.

• Diseases of the exocrine pancreas.
The word ‘diabetes mellitus’ [1] means, ‘excessive excretion
of sweet urine’. Diabetes mellitus is a group of metabolic Endocrinopathies, i.e., changes in hormonal secretion
diseases, characterized by hyperglycemia [2] resulting and, Drugs or chemical induced.
from defects in insulin secretion, action or both. Chronic
hyperglycemia of diabetes is associated with long term
TYPES OF DIABETES MELLITUS
damage, dysfunction, and failure of various organs specially
the eyes, kidneys, nerves, heart and blood vessels. Insulin • Insulin dependant or juvenile-onset diabetes mellitus
is either not secreted in sufficient amounts or does not (Type 1 Diabetes mellitus)
effectively stimulate its target cells, hyperglycemia occurs.
In hyperglycemia blood glucose level becomes so high that • Non insulin dependant or maturity-onset diabetes
glucose “spills over” in urine. However, cells starve since mellitus (Type 2 Diabetes mellitus)
glucose stimulated entry into the cells is impaired. Apparent
symptoms of hyperglycemia are excessive thirst and Type 1: Diabetes Mellitus
frequent urination. Chronic hyperglycemia causes damage
to the eyes, kidneys, nerves, heart and blood vessels. Insulin dependent diabetes mellitus (IDDM), i.e., patients
require periodic doses of insulin it can occur at any
age, commonly occurs in children, Characterized by the
CAUSES OF DIABETES MELLITUS marked inability of the pancreas to secrete insulin because
Main causes of diabetes mellitus are: of autoimmune destruction of the beta cells. Kidney
malfunctioning, nerve impairment, cardiovascular disease
• Genetic defects of beta-cell function [3]. and retinal degeneration occur.
http://doi.org/10.22232/stj.2016.04.02.05
 Singh

Type 2: Diabetes Mellitus the effect of increasing blood glucose levels by two pivotal
metabolic pathways within the liver. These two pathways
Type 2 diabetes is non-insulin dependent diabetes mellitus are by breakdown of glycogen stored in the liver and hepatic
(NIDDM). It accounts for about 90% of the diagnosed cases gluconeogenesis. Glucagon also appears to have a minor
of diabetes and affects 18% of the population over 65 years effect of enhancing lipolysis of triglyceride in adipose tissue
of age. Insulin receptors on insulin responsive cells do not by providing fatty acid fuel to most cells.
respond normally to insulin and are therefore called as
“insulin resistant”, thereby increasing blood glucose level. Glucagon antagonist has been investigated as potent
anti-diabetic agents. The drugs being investigated in the
patients with poorly controlled type-2 diabetes (1 and 2
GESTATIONAL DIABETES Fig. 1).

Gestational diabetes is ‘any degree of glucose intolerance with N

onset or first recognition during pregnancy’. The risk factors O S

associated with developing gestational diabetes [4] mellitus
N
includes the previous diagnosis of gestational diabetes
mellitus. Overweight, obese or severely obese increases the H
risk by a factor 2.1, 3.6 and 8.6, respectively [5].
HO

Insulin
HO
The major function of insulin is to counter the concerted
1
action of a number of hyperglycemia-generating hormones
HO
and to maintain low blood glucose levels. Because there
are numerous hyperglycemic hormones, untreated
disorders associated with insulin generally lead to severe
hyperglycemia and shortened life span.

Insulin is stored in the body in the unit of six molecules

F
but the active one is monomer. Insulin can aggregate and
form interdigitated beta-sheets that can cause injection
amyloidosis, and prevents the storage of insulin for long
periods [6].

Use of Insulin for Treatment of 2

Fig. 1
Diabetes
According to UK perspective on diabetes study, insulin or its ORAL HYPOGLYCEMIC AGENTS
analogues are the standard treatment for type 1, gestational
and some type of type 2 diabetes. The most common and
First and Second Generation
serious reaction of insulin treatment is hypoglycemia. Sulfonylureas (SUs)
Severe hypoglycemia may lead to convulsions and coma. The first-generation SUs include tolbutamide,
It is now known that hypoglycemia kills neurons more acetohexamide, carbutamide, metahexamide, tolazamide
actively than starvation [7]. and chlorpropamide (Fig. 2) and they are rarely used
nowadays due to their severe side-effects. The major
Glucagon Antagonists side-effects induced by SUs include hypoglycemia or even
coma and binding to cardiac receptors, resulting in the failure
Glucagon has a major role to maintain normal concentrations of coronary vasodilatation and subsequent deleterious
of glucose in blood. Glucagon is having the opposite effect cardiac effects due to low specificity of the biological action,
of insulin to maintain glucose level in blood. Glucagon has delayed time of onset and the long duration of the effect [8].

114
 An Overview on Anti Diabetic Drugs and Development

O H
N NH
HN S

HN O O
HN
HN O

O HN
O S O HN
HN O
Cl
O
O S O
O S O
O

Glibornuride
O

H H
N N S
O
NH2 Cl O
O

Acetohexamide Carbutamide Chlorpropamide

Glyclopyramide
H O
N
N O S

HN O
HN HN NH

NH

O O
O HN
HN HN O N

HN S O
O S O O S O
O

Glimepiride
O H H
N N
S
H2N
O O

Metahexamide Tolbutamide Tolazamide

Fig. 2 HN

Second-generation SUs exhibit much safer and N

O

better biological effects, which is achieved by selective

binding and a rapid onset of action. These improvements N

address the issues of SU induced hypoglycaemia as well Glipizide

as cardiovascular side-effects. The second generation
SUs include glibenclamide (glyburide, Diabeta, Glynase
and Micronase; Pfizer), glibornuride, glipizide (Glucotrol; O H
N NH
Pfizer), gliquidone, glisoxepide, glyclopyramide, glimepiride S

(Fig. 3). O O

O O

Cl S NH N

H
N O
O
N
O

Glibenclamide Gliquidone

115
 Singh

H H NO2
O N N
O
S N N
O O
O N S
H
N S
O H3C O
N 3
H
NO2
O
N
Glisoxepide
Fig. 3 N S
H
The sulfonylureas used as hypoglycemic agent is usually H3CH2CO
S
O
p-substituted aromatic compounds with bulkier attachment 4
on nitrogen of urea moiety; small substituents are usually F
not active. They stimulate the release of insulin from β O
cells. Mode of action of sulfonylureas is by affecting ATP
S N OH
sensitive potassium channel which is a complex of two sub H
units; a sulfonyl urea receptor and rectifying potassium
O
channel. Sulfonylurea exhibits both insulin-secreting as
F
well as extrapancreatic activities. Tolbutamide binds well 5
to sulfonylurea receptor [9], metabolism occurs in liver, Fig. 5
where tolbutamide and tolazamide undergo a rapid benzylic
Endothelial dysfunction and consequent reduction
oxidation leading to inactive benzoic acid derivatives (Fig. 4).
of biosynthesis of endogenous nitric oxide (NO) play
O O

O HO O
an important pathogenetic role in the cardiovascular
H3C S NH HN R2 S NH HN R2
complications associated with type II diabetes. The
pharmacodynamic characterization of drugs D and E [14]
O O
Active showed increasing hypoglycaemic activity with additional
NO-donor effects, conferring vasorelaxing and anti-platelet
properties of potentially great usefulness for diabetes-
related cardiovascular disorders.
O

HO O
Both first and second generation sulfonylureas have the
S NH HN R2 same clinical effectiveness but large difference in potency.
O
O These drugs produce a reliable glucose reduction in type 2
Inactive
diabetes (6 & 7 in Fig. 6).
Fig. 4: Mettabolism of Tolbutamide Cl

Various 2-arylsulfonylaminobenzothiazoles were

synthesized and evaluated [10] for their protein tyrosine
H
phosphatase-1D inhibitory activity. Compounds 3 and N

4 have exhibited most promising activity as mixed-type MeO O

inhibitors of PTP-1D. The in vivo anti-hyperglycemic

activities of these compounds make them a suitable leads H
S N
to develop new chemical entities for potential use in the O H
N
O
treatment of T2DM. Also N-(3, 5-Difluoro-4-hydroxy-phenyl) O

benzenesulfonamide (5) [11] exhibited a comparatively O

improved aldose reductase inhibitory activity as well high

O
antioxidant potential. Antioxidant property of compound
5 is additional indication for the ability of a compound to
inhibit the formation of advanced glycation end products
(AGEs) [12], that are implicated in the development of the ONO
2

long-term complications of diabetes [13]. Fig. 6: 6; Meta, 7; Para.

116
 An Overview on Anti Diabetic Drugs and Development

Recently, new series of SUs were studied and found some lactic acidosis, including kidney disorders, lung disease and
potent compound (Fig. 7). Expression of this compound on liver disease. Metformin is often used in combination with
PPAR-γ target genes were measured in 3T3-L1 fibroblasts other oral antidiabetic drugs.
and it was found better in comparison to standard drugs,
The most popular combination of metformin is used
rosiglitazone and glibenclamide. The compound shows
with rosiglitazone. Metformin is also used in combination
significant enhancement in the expression of PPAR-γ
with pioglitazone, glipizide, glibenclamide or glyburide,
genes [15].
dipeptidyl peptidase (DPP)-4 inhibitors sitagliptin,
saxagliptin, meglitinide repaglinide and Novo Nordisk.
CH3
Furthermore, the Food and Drug Administration (FDA)
S
also approved the combination of metformin and alogliptin
under the trade name Kazano in 2013.
N
N
S CH3 NH NH
O
H H
N N
S
N N NH2 H2N
O O H H

Fig. 7
Phenformin
Biguanides
NH NH NH NH
Biguanides are oral agents used for the treatment of mild
to moderately severe T2DM patients to overcome insulin
resistance, especially in obese patients who fail diet and
exercise therapy (Fig. 8) N[16,17]. Biguanides
N have a twofold
NH2 H2N N N(CH3)2
mechanism of action: (i)Hthey enhance H peripheral muscle H
glucose uptake and utilization by making muscle and fat
cells more sensitive to available insulin; and (ii) they inhibit
Phenformin
hepatic glucose output by preventing the liver from making
Metformine
Metformine
excessive glucose [18]. Biguanides are usually associated Fig. 8
with a low risk of hypoglycemia, even in overdose, due to
the fact that insulin secretion is not promoted. Bile Acid Seuestrants
Biguanides are described as insulin sensitizers. Complete Cholestyramine and colestipol are first-generation bile acid
mechanism of action of biguanides is still not clear but it sequestrants and antihyperlipidaemic agents that currently
acts in liver by decreasing excessive glucose production via have a limited use due to their weak effect on lowering
reduced gluconeogenesis resulting from increased sensitivity low-density lipoprotein cholesterol (LDL-C) and poor
of insulin [19]. The main action of biguanide drugs appears tolerability [23,24]. The second-generation bile acid
in the liver mitochondria via activation of adenosine-5’- sequestrants, such as colesevelam and colestimide (also
monophosphate-activated protein kinase (AMPK) [20]. The called colestilan) have a glucose-lowering effect and
therapeutic effect of metformine requires the presence of improved tolerance, which has led to re-evaluation of their
insulin and metformine does not stimulate the release of application as oral antidiabetic agents. Colesevelam is a bile
insulin or other factors, such as glucagon. In fact, metformine acid-binding resin sequestrant, it is indicated as an adjunct
suppress the secretion of adiponectin, an insulin-sensitizing to diet and exercise to reduce elevated LDL-C in patients with
hormone [21]. Metformin is not metabolized and is cleared primary hyperlipidaemia as monotherapy and to improve
from the body by tubular secretion mediated by organic glycaemic control in T2DM, including in combination with
cation transporters and is excreted unchanged in the a statin [25,26]. The mechanism by which colesevelam
urine [22]. Metformin has a low risk of causing hypoglycaemia improves glycaemia has not been fully understood but
and lactic acidosis. However, metformin is contraindicated may involve enhanced meal-induced incretin secretion and
in people with any condition that could increase the risk of altered farnesoid X receptor (FXR) signaling [24,26].

117
 Singh

Gliptins (DPP-4 Inhibitors) that have a glucose-dependent dual action on α- and β-cell
functions, stimulating insulin secretion and suppressing
Dipeptidyl peptidase-4 (also known as adenosine deaminase glucagon secretion under hyperglycaemic conditions.
complexing protein 2 or CD26) cleaves the two N-terminal This dual action of incretin leads to an improved time-
amino acids from peptides with a proline or alanine course of islet hormone secretion after a meal as well as in
in the second position, and inactivating both glucagon- hyperglycaemia. The discovery of incretin therapy may help
like peptide-1 (GLP-1) and gastric inhibitory polypeptide overcome the limitations of the classical treatment options
(GIP) [27, 28]. Endogenously released GLP-1 has a short for T2DM.
biological half-life around 1.5–5 min, whereas the serum
half-life of GIP is approximately 7 min [29]. Upon secretion
of GLP-1 and GIP both are rapidly degraded and inactivated Dopamine D2 Receptor Agonists
by DPP-4. Therefore, DPP-4 inhibitors (Fig. 9) have been (Bromocriptine)
developed and to prevent degradation of endogenously
Bromocriptine (Fig. 10), a central-acting dopamine D2
released GLP-1 and GIP. Consequently, it enhanced plasma
receptor agonist used for the treatment of T2DM in 2009 [31].
concentrations of active incretin, prolonging the actions of
This drug has been previously widely used in treatment of
the incretin and leading to increased insulin levels [30].
O
hyperprolactinaemia and galactorrhoea caused by pituitary
tumours, Parkinson’s disease, hyperprolactinaemia and
N neuroleptic malignant syndrome [31].
H2N
N N O
O

N
N O
N

Alogliptin
O
H HO
NH2 O F O
F NH
F N N F
N
F
N O
N

H
F F
F

Gemigliptinz

Br
N
H2N N
N
H
N
N Fig. 10
N

N
N The mechanism of action underlying how bromocriptine
N N
regulates glycaemic control is not clear, but data indicate
that bromocriptine improves insulin sensitivity and other
Linagliptin metabolic abnormalities [32]. Bromocriptine is a potent
Fig. 9 agonist at dopamine D2 receptors, serotonin (5-HT1, 5-HT2
The insulin-releasing effects of incretins are glucose and 5-HT6) receptors and α1- and α2-adrenoceptors. In
dependent and the incretins have no insulinotropic activity addition, it is also a moderate agonist for dopamine D1
at lower glucose concentrations (< 4 mmol/L), thus it receptors and 1- and 2-adrenoceptors [31,32]. Bromocriptine
reduces the chance of hypoglycaemia, which is one of inhibits glucose-stimulated insulin secretion by direct
the major concerns with other antidiabetic drug classes. activation of α2-adrenoceptors on β-cells [33]. Clinical
Furthermore, DPP-4 inhibitors are the first substances studies have shown that quick release (QR) bromocriptine

118
 An Overview on Anti Diabetic Drugs and Development

lowers HbA1c by 0.6%–1.2% either as monotherapy or in forms a secondary hydrogen bond with H323. The partly
combination with other antidiabetic drugs [31]. negatively charged nitrogen of the TZD head group is within
hydrogen bonding distance of the Y473 side chain hydroxyl
group. A buried lysine residue, K367, forms another
Peroxisome Proliferator-Activated secondary hydrogen bond with rosiglitazone, at residue
Receptors (PPARs) H449. All of these primary and secondary hydrogen bonds
The peroxisome proliferator-activated receptor result in a fixed conformation of the TZD head group and of
belongs to the family of nuclear receptors including the participating amino acids. Next to the head group, the
the oestrogen receptors, thyroid hormone receptors, sulphur atom of the TZD ring is positioned in a hydrophobic
retinoic-acid receptors (RARs) and retinoid-X receptors region of the PPAR-γ. After activation by specific ligands,
(RXRs) [34]. PPARs are the group of nuclear receptors PPARs binds to the regulatory regions of DNA of the genes,
that control the carbohydrate metabolism by altering the thus regulating the transcription of genes involved in
expression of the genes involved, consists of three different glucose homeostasis pocket formed by F363, Q286, F282
genes, PPARα, PPARβ/δ, PPARγ. PPARα shows distinct tissue and L469. The central benzene ring of the ligand occupies
distributions [35, 36] and associated with different ligands a very narrow pocket between C285 and M364. The
[37]. These are highly expressed in liver, skeletal muscles bridging oxygen atom between the benzene ring and the
and heart, PPARγ is highly expressed in adipose tissues but pyridine ring provides vital geometry for the pyridine ring,
is also expressed in intestines, breast tissues etc. PPARβ/δ which occupies the pocket between H3 and the β-sheet.
is expressed in highest level in skin and skeletal muscle. At Rosiglitazone has one chiral atom in the head group that is
submicromolar levels, a class of thiazolidinediones (TZDs) in the S configuration, even though a racemic mixture was
activates PPAR-γ and are used pharmaceutically for the used for crystallization. Substituted carboxylic acids can
treatment of type 2 diabetes because they sensitize tissues act as bio-isosteric replacements for the TZD head group,
to insulin.[38] PPAR-γ may be the biochemical target of maintaining high affinity binding and receptor activation.
TZDs [39]. PPAR-γ contains the general structural features of It is predicted by above findings that these carboxylic acids
other nuclear receptor-family members, including a central conserve the key interactions with H323 and H449, and
DNA-binding domain and a carboxy-terminal domain that that this molecular recognition may be important for the
mediates ligand binding, dimerization and transactivation binding of other acidic ligands. Several naturally occurring
functions. carboxylic acids, including essential fatty acids, oxidized
lipids and prostaglandin J2 metabolites, can bind and
activate PPAR-γ at micromolar concentrations.[41] According
to above studies, it is proposed that all of these hydrophobic
carboxylic acids bind to PPAR, and that the key interactions
involving the histidine residues required for TZD binding
are conserved with the acid groups.

The treatment generally prescribed for non-insulin

dependent diabetes mellitus (NIDDM) is a combination of
diet, exercises, and oral hypoglycemic agents, commonly
sulfonylurea and biguanides [42]. However, sulfonylurea
Fig. 11: Binding of Rosiglitazone with PPARγ.
therapy leads to many problems associated with primary
Rosiglitazone, antidiabetic drug of glitazone series, and secondary failure of efficacy, incidence of hypoglycaemia
occupies about 40% of the ligand-binding [40] site in the [43] and obesity [44]. Thus, drugs that reverse the onset of
ternary complex. In general, the ligand is in a U-shaped insulin resistance fulfil a major unmet medical need for the
conformation, wrapping around H3 with its central treatment of NIDDM [45]. Replacement of the thiazolidine-
benzene ring directly behind H3 and the TZD head group 2,4-dione ring by an isoxazolidine-3, 5-dione (JTT-501)
and pyridine ring wrapping around H3 (Fig. 11). The TZD (Fig. 12) [46, 47] and its non-cyclic 1, 3-dicarbonyl
head group makes several specific interactions with amino derivatives (JTP20993) and compound 8 (Fig. 12) [48]
acids in H3, H4, H10 and the AF-2 helix (Fig. 11). The led to compounds which showed very interesting insulin-
carbonyl groups of the TZD form hydrogen bonds with two sensitizing activity in 3T3-L1 cells and hypoglycemic activity
histidine residues, H323 and H449. Y473 in the AF-2 helix in genetically diabetic KKAy mice.

119
 Singh

O
carboxylic anionic head of acids at 3-position with the
carboxamide or N-hydroxycarboxamide group produces
CH3 OCH3
O a general decrease in the in vitro ALR2 inhibitory effect,
O O OCH3
whereas insertion of the N-hydroxyacetamide chain on N-3
N (compounds 10) gave a general improvement in activity.
CH 2 CONH 2 CH 2 CONH 2 CH 2 CONHOHCH 2 CONHOH
JTP20993 O O
N O O
N N N
O
O O O O
CH3
O S S S S
O
O O N
H
N

Ar Ar Ar Ar

JTT-501 10 11
O Fig. 14
The main side effect of glitazones is water retention
HN
H leading to edema, with significant water retention, leading
S N
O to decompensation of potentially previously unrecognized
O
O OH
heart failure. Recent studies have shown there may be
O increased risk of attack with rosiglitazone. Pioglitazone
O treatment, in contrast, has shown significant protection from
8 both micro and macro-vascular cardiovascular events and
Fig. 12 plaque progression. These side effects are the requirement
A series of benzazolonic heterocycles, which could of development of new molecules with potent antidiabetic
replace the 2-phenyloxazole of JTP20993, bearing a 1, activities with least side effects.
3-dicarboxylic functionality as potent and selective PPARγ Saroglitazar was the first glitazar to be approved for the
agonists have been synthesized [49] and the SAR studies treatment of T2DM. It is marketed under the trade name
demonstrated that 2(3H)-benzothiazolone seemed to be the Lipaglyn. The average terminal half-life of saroglitazar
most potent nitrogen heterocycle of the series (9). is 5.6 h and it is not eliminated via the renal route [52]
O
Single oral doses of saroglitazar up to 128 mg are well
O
tolerated [52] Bezafibrate is a fibrate drug used for the
S OCH3
treatment of hyperlipidaemia. It helps lower LDL-C and
N triglyceride and increase HDL in the blood. Like the other
O OCH3
R
O fibrates, bezafibrate is a PPARα agonist; some studies
O
suggest it may also have modulating effects on PPARγ and
9 PPARδ [53,54].
Fig. 13
The recent discovery that peroxisome proliferator-
The Aldose reductase (ALR2) inhibitory data of activated receptor γ (PPAR γ) targeted anti-diabetic drugs
some 5-arylidene-2, 4-thiazolidinediones [50] can be function by inhibiting Cdk5-mediated phosphorylation of
considered as promising ARIs and allowed to extend their the receptor has provided a new viewpoint to evaluate and
structure–activity relationships. The introduction of an perhaps develop improved insulin-sensitizing agents. As the
additional aromatic ring or an H-bond donor group on the prevalence of obesity continues to rise, therapies started to
5-benzylidene ring was shown to be very favourable for treat the metabolic syndrome and its associated conditions
the ALR2 inhibitory effectiveness of these compounds. The are of increasing importance. Novel thiazolidinedione
in vitro evaluation of (5-arylidene-2, 4-dioxothiazolidin-3-yl) (GQ-16), that retains similar anti-diabetic efficacy as
acetamides (10) [51] and analogous N-hydroxyacetamides rosiglitazone in trial yet does not elicit weight gain or
(11) (Fig. 14) highlighted that the replacement of the edema, common side effects associated with full PPAR γ

120
 An Overview on Anti Diabetic Drugs and Development

activation. Further characterization of this compound shows S

GQ-16 (Fig. 15) to be an effective inhibitor of Cdk5-mediated HO OH
phosphorylation of PPAR γ [55].
Br
O
F OH
S
O
N

OH

Ipragliflozin
O
O Cl O

O
Fig. 15. (GQ-16). HO

SGLT2 Inhibitors: A New Class of HO OH

Diabetes Medications OH

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a Dapagliflozin

new class of diabetic medications used for the treatment of Fig. 16
type 2 diabetes. SGLT2 is a protein in humans that facilitates
glucose reabsorption in the kidney. SGLT2 inhibitors lower CONCLUSION AND FUTURE DIRECTION
blood glucose level by blocking the reabsorption of glucose
in the kidney and increasing the glucose excretion [56]. Despite the fact that now a variety of antidiabetic agents
Inhibition of SGLT2 leads to the decrease in blood glucose are available for the treatment T2DM patients albeit there
due to the increase in renal glucose excretion. This class of are shortcomings in diabetes treatment at present and the
drugs offers further glucose control by allowing increased search for optimal therapy is ongoing. Putting aside common
insulin sensitivity and uptake of glucose in the muscle cells, side-effects, such as weight gain and hypoglycaemia,
decreased gluconeogenesis and improved first phase insulin current diabetes therapies do not address the key driver of
release from the beta cells. this condition, namely β-cell dysfunction, and do not alter
the progressive nature of the insulin secretory deficit. In
Drugs in the SGLT2 inhibitors class include empagliflozin,
addition, the pathophysiology of the disease is only partially
canagliflozin, dapagliflozin, ipragliflozin (Fig. 16) [57]. There
understood and there are currently no antidiabetic agents
are many side effects but vaginal yeast infections and urinary
that can effectively reduce excessive cardiovascular risk
tract infections are the most common side effects associated
associated with T2DM. Therefore, development of new
with these inhibitors with the greatest risk being in female
antidiabetic drugs should not only address blood glucose
patients and those men who are uncircumcised [58].
levels, but also aim to halt disease progression, restore
β-cell function and, in the long run, reduce T2DM-associated
O F
complications, such as cardiovascular risks. In conclusion,
HO S
the examples highlighted in this review convincingly
demonstrate the short comings of antidiabetic therapy,
HO OH while at the same time they emphasize the need for truly
OH new safer and effective antidiabetic drugs.
Canagliflozin
OH

HO OH
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