19:56 Firda L.

Safna i am die -_-

Pharmacological Treatment of DM

Pancreatic β cell is destroyed in T1DM which causes an absolute defi ciency of

insulin in the body. Thus, T1DM necessitates insulin treatment soon after the
detection of the disease, and subsequently insulin treatment should be continued
without interruption for lifelong. On the other hand, T2DM results from the
decrease in insulin secretion or insulin resistance. Several oral hypoglycemic
agents like sulfonylureas, biguanides, meglitinides, thiazolidinediones, and α-
glucosidase inhibitors are the choice of drug to treat T2DM along with insulin. But
in last few years, advancement of medical science gifted us several other oral
hypoglycemic agents (DPP-4 inhibitors, SGLT2 inhibitors) and injectable (GLP-1
analog, amylin analog) antidiabetic drug

to treat T2DM, which offers an opportunity to treat/manage DM and its

complications in a better way. Currently available antidiabetic drugs are classifi
ed as:

1. Injectable antidiabetic agents (a) Insulin (b) Amylin analog :

Pramlintide (c) Glucagon-like peptide-1 ( GLP - 1 ) analog : Exenatide and
liraglutide 2. Oral hypoglycemic agents (a) Sulfonylureas : First-
generation sulfonylureas: Tolbutamide, chlorpropamide, and acetohexamide
Second-generation sulfonylureas: Glimepiride, glibenclamide, gliclazide, and
glipizide ( b) Meglitinides : Repaglinide and nateglinide (c) Biguanides :
Metformin (d) Thiazolidinediones : Pioglitazone and rosiglitazone (e)
PPARα and PPARγ agonist : Saroglitazar (f) α - Glucosidase inhibitors :
Acarbose, miglitol, and voglibose (g) Dipeptidyl peptidase-4 ( DPP - 4 )
inhibitors: Sitagliptin, saxagliptin, vildagliptin, linagliptin, and alogliptin (h)
Sodium - glucose co - transporter 2 ( SGLT2 ) inhibitors : Canaglifl ozin, dapaglifl
ozin, empaglifl ozin, ipraglifl ozin, and tofoglifl ozin

Insulin

Insulin treatment is the mainstay for the management of not only for T1DM but
also for T2DM. In type 1 diabetic patients, insulin and insulin analog are
considered as an only treatment strategy, while in type 2 diabetic individuals,
insulin is used along with other hypoglycemic agents. Insulin can be given through
intravenous or intramuscular route, but usual and long-term treatment prefers
subcutaneous injection of insulin. Different insulin preparations available in the
market differ in a several way, including variation in recombinant DNA production
methods, a sequence of amino acid, solubility, concentration, onset time, and
duration of their biologic effect. In a usual strategy, insulin injections are given
one or two times a day. About 2/3 of the total daily dose is given before
breakfast/morning food, and remaining 1/3 is given before dinner. In intensive
insulin treatment, strategy includes administration or insulin ≥ three times/day
through injection, external pump, or pen. Insulin dose is adjusted as per premeal
blood glucose level. Insulin is absorbed quickly from the abdomen followed by the
arms, thigh, and buttock. It is appropriate to inject the insulin within one area
rather than administering to different areas, as its day-to-day absorption differs.
Exercise stimulates the absorption rate from the site of injection. Several new
techniques like an artifi cial pancreas, buccal and oral insulin, inhalable insulin,
transdermal insulin as patches, and intranasal insulin are in the developing stage
to deliver the insulin other than the subcutaneous route. Hypoglycemia, weight
gain, allergy reaction, infection, injection site abscess, lipoatrophy, insulin edema,
lipohypertrophy, and insulin resistance are the common problems associated with
insulin injection (Table

11.1 ) (Davis 2006 ; Yadav and Prakash 2006 ; Joshi et al. 2007; Richard et al.
2009 ; Katzung et al. 2012 ; Azad et al. 2013 ).

Amylin Analog

Amylin is a naturally derived peptide and is also known as islet amyloid

polypeptide (IAPP).

Amylin is mainly produced and synthesized by β cells of islet of Langerhans and

colocalized with insulin. Amylin and insulin are released from β cell in response to
food intake in a molar ratio of ~1–100 in normal individuals. Expression of amylin
is also observed in the gut and sensory nervous system. Amylin suppresses
postprandial glucagon secretion, induces satiety, delays gastric emptying, and
reduces intake of food and body weight. Pramlintide is a soluble analog of amylin
used in the patient with T1DM and T2DM as an adjunct treatment strategy.
Usually, pramlintide is used in the patient to whom mealtime insulin therapy or
sulphonylurea and/or metformin therapy failed to achieve expected antidiabetic
effect. Pramlintide acts through central pathways by acting on the amylin
receptors present in the area postrema of the brainstem. Amylin agonists also
may exhibit few benefi cial effects of GLP-1. Pramlintide helps insulin to achieve
proper postprandial glucose homeostasis and maintain the glucose level in blood.
Pramlintide suppresses glucagon secretion from α cell and thus decreases hepatic
glucose release, delays the rate of gastric emptying, decreases release of gastric
acid and pancreatic juice, and thus retards the digestion rate but not overall
absorption of nutrient. Pramlintide has moderate effect on HbA1C reduction, but
exerts favorable effect in reducing food intake and body weight (Reda et al.
2002 ; Day 2005 ; Messer and Green 2009 ).

Glucagon-Like Peptide-1 (GLP-1)

Incretins are a group of gastrointestinal hormones that have a signifi cant effect
in the maintenance of blood glucose levels. Glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic polypeptide (GIP) are recognized as two main
incretin hormones. In response to carbohydrate- and lipid-containing meals, GIP
and GLP-1 are secreted from the intestine and play a key role to stimulate insulin
release from the pancreas. GLP-1 exists in two different molecular forms in the
circulation, GLP-1(7-37) and GLP-1(7-36) amide, although the latter one is more
copious in the circulation after intake of food. The major source of GLP-1 is
enteroendocrine L cells of the distal ileum and colon. Both GIP and GLP-1 bind
with of structurally distinct GPCRs such as GIP receptor (GIPR) and GLP-1 receptor
(GLP-1R). Activation of these receptors result increase in cAMP level in β cell,
thereby stimulate glucose- dependent insulin release. GIPR is mostly expressed on
pancreatic β cells and also in adipose tissue and in the CNS but in a lesser extent.

In contrast, GLP-1R is expressed in pancreatic α and β cells and in several other

tissues like the CNS, heart, kidney, lung, and GIT. Incretin receptor signaling is also
related with pKA activation, initiation of gene transcription, an increase in insulin
biosynthesis, and β-cell proliferation stimulation. Activation of GLP-1R and GIPR
endorses resistance to apoptosis and increased survival of β cell. GLP-1 also
restrains secretion of glucagon,

gastric emptying, and ingestion of food and causes glucose removal through
neural mechanisms. Type 2 diabetic people have distinctly blunted incretin
secretory action which may be responsible for impaired postprandial insulin
release by up to 60 %. The α cell of the islet in the pancreas downregulates
glucagon secretion through augmentation of incretin system. Thus, it can be
proposed that paralysis of incretin axis in type 2 diabetic patient may result in
high postprandial and fasting blood glucose level. GIP is found comparatively
ineffective in stimulating release of insulin in people with T2DM, while GLP-1
increases secretion of insulin in both nondiabetic and diabetic individuals and
promotes glucose homeostasis beyond the enhancement of insulin release. Thus,
GLP and GLP-1 analog have been pursued as a therapeutic agent (Drucker and
Nauck 2006; Seino and Yabe 2013) . C urrent researches have showed the
importance of GLP-1 and the agonist of GLP-1R in the management of T2DM. Very
short half-life (1.5 min) is the major limitation of endogenous GLP-1. Dipeptidyl
peptidase-4 (DPP-4) causes proteolytic degradation of GLP-1 rapidly by cleaving
the active GLP-1 (7–36) to inactive GLP-1 (9–36). Short-term intravenous
administration of GLP-1 reduces blood glucose level in type 2 diabetic patient. But
such measures are helpful while controlling diabetic condition for short term.
Exenatide and liraglutide are the examples of GLP-1R analog used to treat T2DM
(Drucker and Nauck 2006 ; Thompson and Kanamarlapudi 2013 ). Exenatide, a
synthetic analog of exendin-4, was approved by the US Food and Drug
Administration (FDA) and European Union (EU) in 2005 and 2006, respectively.
Exendin-4 is a biologically active peptide of 39 amino acids discovered from
Heloderma suspectum (a lizard) venom, bearing a 53 % homology to GLP-1 of
human. Exenatide and exenatide LAR (sustained release) are the common forms
available for T2DM. Exenatide is a short-acting GLP-1R agonist marked in 5–10 μg
pen and prescribed twice a day before meals. Treatment with exenatide is

found to reduce in HbA1c, decrease fasting and postprandial plasma glucose level,
and reduce body weight (Drucker and Nauck 2006 ; Gupta
 2013 ; Thompson and Kanamarlapudi 2013 ). Liraglutide is an acylated analog of
GLP-1 and also acts as DPP-4 resistant partly. It was approved by the EU, Japan,
and USFDA in 2009 and 2010. Liraglutide is a long-acting drug acting on GLP-1R
and administered subcutaneously once a day. Liraglutide reduces postprandial
blood glucose and body weight without the risk of hypoglycemia (Drucker and
Nauck 2006 ; Vilsboll et al. 2008 ; Lambert 2013 ; Gupta 2013 ). I n general, GLP-
1R agonist is not responsible for hypoglycemia on their own, but when
administered with other antidiabetic drugs like sulphonylureas, the risk of
hypoglycemia may exist. Nausea and vomiting are the usual adverse effect of
these drugs, but in case of transient nausea, up-titrating the dose slowly is
essential (Lambert 2013 ). Several other drugs like lixisenatide (human GLP-1R
agonist) developed by Sanofi Aventis under license from Zealand Pharma are
undergoing phase 3 clinical trials. Albiglutide (GLP-1 mimetic effect and resistant
to DPP-4) is under phase 3 clinical trial developed by GlaxoSmithKline. Dulaglutide
(long-acting GLP-1 analog) is under investigation developed by Eli Lilly (Gupta
2013 ; Thompson and Kanamarlapudi 2013 ). Current investigations also
highlighted the positive effect of GLP-1 agonist and several macrovascular
complications of diabetes. GLP-1 can avert cerebrovascular disease, endothelial
dysfunction, peripheral artery disease, and coronary artery disease, through their
distinct measures on the brain, vascular endothelial cells, and heart. Indirectly,
GLP-1 also produces a positive effect through regulation of blood pressure, infl
ammation, and metabolism of lipid. GLP-1 agonist can also reduce the oxidative
stress and may be involved in controlling obesity or intake of excessive food
through meal enteroenteric refl exes and across meal central signaling
mechanisms (Goyal and Kumar 2010 ; Dailey and Moran 2013 ; Seino and Yabe
2013 ) (Fig. 11.1 ).

Sulfonylureas

History and Chemistry Hypoglycemic effect of synthetic sulfur compounds was

investigated in 1937 by Ruiz and his colleagues. In 1942, a French physician
Marcel Janbon and his colleagues found that sulfonylurea produces hypoglycemic
effect in patients administered with
 p -amino-sulfonamide-isopropylthiodiazole for typhoid. Lobatieres and his
colleagues in 1946 reported that this type of drugs stimulates β cell and induces
release of insulin. In between 1954 and 1956, tolbutamide (fi rst generation of
sulfonylurea) was introduced in the USA and Germany followed by
chlorpropamide. In 1984, second- generation sulfonylureas like glyburide and
glipizide were discovered. In 1995, glimepiride, another potent second generation
of a drug, was introduced (Stingl and Schernthaner 2007 ; Quianzon and Cheikh
2012 ).

Mechanism of Action Sulfonylurea receptor (140-kDa) is associated with β cell

which is considered as a subunit of the voltage-dependent potassium ATP (K ATP)
channels on pancreatic β cells. Sulfonylureas act on sulfonylurea receptor 1
(SRU1, a part of a transmembrane complex with ATP Kir 6.2 potassium channels)
and inhibit the effl ux of K + through the channel, which

induces depolarization. This depolarization induces the opening of voltage-gated

Ca 2+ channels. Increase in the intracellular Ca 2+ results in the release of
preformed insulin from the granules of β cell. There is some support that
sulfonylureas also enhance peripheral insulin sensitivity, reduce the production of
hepatic glucose production, and reduce serum glucagon level indirectly (Cheng
and Fantus 2005 ; Nolte and Karam 2007 ; Stingl and Schernthaner 2007 ).

Pharmacokinetic Profi le Sulfonylureas are absorbed from the GIT effectively

though food and hyperglycemia may retard the absorption. They are more
effective when administered 30 min before food. Sulfonylureas have high (90–99
%) plasma protein (especially albumin) binding capacity. Second-generation
sulfonylureas are more effective than the fi rst generation of drugs. These drugs
are metabolized in the liver and excreted through urine. Tolbutamide is absorbed
rapidly and has an elimination halflife of 4–5 h. Chlorpropamide is metabolized
slowly and has a half-life of 32 h. Half-life of glipizide is about 2–4 h, shortest
among the potent agents. Among sulfonylurea compounds, glimepiride required
the lowest dose to produce hypoglycemic effect (Davis 2006; Rang et al.

Uses, Adverse Effects, Contraindication, and Precautions Sulfonylureas are used

to control blood sugar level in type 2 diabetic people. These drugs are used as
monotherapy (along with proper diet) and in combination with insulin,
metformin, and other oral antidiabetic drugs. Sulfonylureas, when used with
metformin, may reduce HbA1c very effectively. Sulfonylureas should be
introduced as low dose. Hypoglycemic effect is the common side effect of
sulfonylurea. However, second-generation drugs have very differing frequency of
hypoglycemia. Weight gain, hyperinsulinemia, nausea, vomiting, agranulocytosis,
cholestatic jaundice, anemia (aplastic and hemolytic), hypersensitivity, and
dermatological reactions are the other side effects of sulfonylurea. Some
sulfonylurea drugs like glyburide may cause renal impairment (Davis 2006 ; Nolte
and Karam 2007 ; Richard et al. 2009 ).

Nonsteroidal anti-infl ammatory drugs, coumarins, sulfi npyrazone, alcohol,

monoamine oxidase inhibitors, sulfonamides, trimethoprim,

chloramphenicol, and few imidazole antifungal agents may reduce the blood
glucose level when administered with sulfonylureas. Thiazide diuretics and
corticosteroid may reduce the action of sulfonylureas. Precaution has to be taken
while administering sulfonylureas in patients with renal or hepatic insuffi ciency.
These agents except glibenclamide can cross the placenta and can initiate fetal
islet to release insulin, which in turn is responsible for severe hypoglycemia at
birth (Davis 2006 ; Rang et al. 2003 ; Richard et al.

2009 ) (Fig. 11.2 ).

Meglitinides

These drugs are known as non-sulfonylureas and exert almost same mechanism
of action like that of sulfonylureas. However, they may attach to sulfonylurea
receptor at a distinct portion. These drugs have a weaker binding affi nity and
quick dissociation rate from the binding site. The fi rst drug of this group is
repaglinide, which is approved for clinical use in 1998. Meglitinides are mainly
considered as postprandial glucose regulator in type 2 diabetic patient which
produce better effect in the early release of insulin after a meal. These agents are
metabolized in the liver through the cytochrome P450 system and excreted
through bile. Meglitinides can be used alone or along with other oral antidiabetic
drugs other than sulfonylureas. Repaglinide is quickly absorbed from the GIT; half-
life is about 1 h. Nateglinide is also absorbed within 20 min after oral
administration, and half-life is about 1.5 h. Major side effects of these drugs
include hypoglycemia, weight gain, and diarrhea. Meglitinides must be used with
care in people with hepatic impairment (Davis 2006; Nolte and Karam 2007 ;
Richard et al. 2009 ).

Biguanides

History and Chemistry Biguanides are the class of oral antidiabetic drug
introduced in 1957 for the treatment of T2DM. Phenformin and buformin are
withdrawn from the market of most of the countries due to toxic effects.
Metformin (dimethylbiguanide) is a well-known antidiabetic drug, the discovery of
which is related to a traditional antidiabetic plant ( Galega offi cinalis ) from
Europe. Galega offi cinalis extract is used to treat DM till the 1930s in France.
Guanidine is a major chemical constituent of the plant which possesses
hypoglycemic effect in animals, but the use of guanidine is restricted due to its
toxicity. In the 1920s, several natural and synthetic analogs of guanidine like
galegine (isoamylene guanidine), decamethylene diguanide (Synthalin A), and
dodecamethylene diguanide (Synthalin B) were discovered, which show
antidiabetic effect and exhibit less toxic effect. Several hypoglycemic biguanides
including dimethylbiguanide were described in 1929. In 1957–1958, metformin
was found effective as an antidiabetic drug and introduced in the market. But in
the 1970s, metformin was removed from market/not approved in several
countries due to its most common side effect lactic acidosis. Metformin was used
widely in Canada and Europe; it was again approved in the

USA in 1995, when the drug satisfi es the safety criteria in Canada, Europe, and
Asia (Bailey

1992 ; Bailey and Day 2004 ; Devis 2006).

Mechanism of Action Precise mechanism of action of metformin is still not

known. But metformin restrains gluconeogenesis, reduces fatty acid and
cholesterol synthesis, increases time for gastrointestinal glucose absorption,
decreases food intake, and reduces body weight of type 2 diabetic obese
individuals. Metformin activates adenosine monophosphate (AMP)-activated
protein kinase (AMPK) in hepatic and muscle tissues. Activation of AMPK results in
increase in glucose uptake and glycogenesis in the muscle, a key area for
metformin effect. Metformin increases AMP-ATP ratio and thus activates AMPK
which results in inhibition of the respiratory chain complex I. Hepatic AMPK
activation results in inhibition of acetyl-coenzyme A carboxylase (ACC) and 3-
hydroxy-3- methylglutarylcoenzyme A (HMG-CoA), thus reducing expression of
fatty acid synthase (FAS) and activation of malonyl-CoA carboxylase. These
changes are responsible for cholesterol and fatty acid synthesis inhibition.
Activation of hepatic AMPK is responsible for reduced expression of sterol-
regulatory-element-binding-protein-1 (SREBP-1), which is playing a key role in
the pathogenesis of insulin resistance, DM, and dyslipidemia. Reduced SREBP-1
expression is also responsible for reduced synthesis of triglyceride and hepatic
steatosis through the reduced gene expression of lipogenic enzymes. Another key
effect of metformin includes suppression of gluconeogenesis in the liver through
the inhibition of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-
phosphatase (G6Pase) transcription. Increase in hepatic SIRT1 (an NAD +
-dependent protein deacetylase) through AMPK-mediated stimulation of
nicotinamide phosphoribosyltransferase also may involve in suppression of liver
gluconeogenesis. Metformin may act on the hypothalamus and reduce AMPK.
Inactivation of AMPK results in inactivation of phosphorylation of ACC and thus
increases the level of malonyl-CoA and suppresses food intake and reduces body
weight (Zhou et al. 2001 ; Cheng and Fantus 2005 ; DiStefano and Watanabe
2010 ; Nakano and Inui

2012 ; Viollet et al. 2012 ).

Pharmacokinetic Profi le Metformin is mainly absorbed in the small intestine.

Bioavailability of metformin is 50–60 %, and plasma t1/t2 is about 2–5 h. Nearly
90 % of drugs are eliminated from the body within 12 h. Metformin does not
attach to plasma proteins and is excreted through urine in unchanged form
(Bailey 1992 ; Cheng and Fantus 2005 ).
 Uses, Adverse Effects, Contraindication, and Precautions Metformin is used to
treat T2DM alone or along with insulin or with other classes of oral antidiabetic
agent. Important side effect of metformin includes lactic acidosis and
megaloblastic anemia. Common side effects are diarrhea, vomiting, dyspepsia, fl
atulence, metallic taste, and weight loss. Alcohol intake may potentiate lactase
metabolism. Metformin is contraindicated in people with renal function
impairment,

cardiac and respiratory insuffi ciency, liver diseases, alcohol abuse, metabolic
acidosis, or condition related to hypoxia or reduced perfusion (Reddy et al. 2000;
Krentz and Bailey 2005 ; Davis 2006 ) (Fig. 11.3 ).

Thiazolidinediones

H istory T hiazolidinediones are also known as glitazones, act as an agonist of

peroxisome proliferator-a ctivated receptor-γ (PPARγ), and increase insulin
sensitivity toward the body tissue via multiple actions on gene regulation.
Antidiabetic effect of thiazolidinediones was reported in early 1980, but
introduced in the market in the late 1990s. Troglitazone was the fi rst drug under
this class marked in the UK and USA in 1997 but withdrawn due to severe
hepatotoxicity reaction. Rosiglitazone and pioglitazone were introduced in USA
and Europe in the year 1999–2000 (Krentz and Bailey Mechanism of Action
Nuclear hormone receptors act by regulation of gene expression in response to
small ligands. Different type of nuclear hormone receptors includes testosterone,
vitamin D, thyroid hormone, bile acids, and retinoic X receptor (RXR). PPARs are
considered as a signifi cant subfamily of nuclear hormone receptors which are
found to regulate the storage and catabolism of dietary fats in large extent. PPARs
regulate the transcription and expression of a specifi c gene. Three subtypes of
PPARs were identifi ed – α, δ, and γ. PPARα is expressed in the liver, kidney,
brown adipose tissue, skeletal muscle, and heart tissue. PPARγ is mostly
expressed in adipose tissues and also found in the muscle, kidney, colon,
pancreas, liver, and intestine. PPARδ is found in the brain, adipose tissue, and skin
and in wide range of tissue. Both PPARα and PPARγ are also expressed in smooth
muscle cells of the blood vessel, endothelial cells, and monocytes/macrophages
and in human atherosclerotic lesions (Singh et al. 2011 ; Javiya and Patel 2006 ).

Thiazolidinediones are lipophilic which enter cells easily and act as ligand for
PPARγ to stimulate insulin sensitivity particularly in the peripheral tissue. PPARγ
acts in association with RXR by producing heterodimer and then attached to
specifi c peroxisome proliferator response elements (PPRE) for activation. Their
activation results in the initiation of regulatory sequences of DNA that regulate
the expression of specifi c genes, which is involved in carbohydrate and lipid
metabolism. Metabolic effects of thiazolidinediones include increase in glucose
uptake in the skeletal muscle and adipose tissue, increase in fatty acid uptake and
lipogenesis in the adipose tissue, preadipocyte differentiation, increase in
lipogenesis in the liver, reduced glycogenolysis and gluconeogenesis in the liver,
and increase in glycolysis and glucose oxidation in skeletal muscle. Thus,
thiazolidinediones play a key role for the treatment of T2DM (Das and Panda
2004 ; Krentz and Bailey

2005 ; Chiarelli and Marzio 2008 ).

Pharmacokinetic Profi le Rosiglitazone and pioglitazone are absorbed

completely and rapidly, though food may delay the absorption rate.

Drugs are metabolized through the liver extensively (Cheng and Fantus 2005;
Krentz and Bailey 2005 ).

Uses, Adverse Effects, Contraindication, and Precautions Rosiglitazone and

pioglitazone can be used as monotherapy in individual with T2DM and can be
used in combination of other drugs and insulin. These drugs also lower the HbA1c
by 1 to 1.6 % in patients with DM. These drugs also may be useful to reduce the
CVS and other complications related to DM. Pioglitazone may be useful to
improve lipid profi le in diabetic subject. Retention of fl uid, gain in body weight,
congestive heart failure, pulmonary edema, and anemia are the side effects
reported after thiazolidinedione treatment. Caution should be taken while using
these drugs in acute liver diseases, in heart failure, in patient receiving insulin,
during pregnancy and breastfeeding, and in polycystic ovary syndrome (Krentz
and Bailey 2005 ; Tack and Smits 2006; Chiarelli and Marzio 2008 ) (Fig. 11.4 ).

PPARα and PPARγ Agonist

P eople with T2DM are at risk of dyslipidemia and overweight. CVS complications
mainly macrovascular disease is responsible for a huge number of mortality in
diabetic patients. Currently available antidiabetic thiazolidinediones act on PPARγ
receptor and mainly act via increasing insulin sensitivity and confer very less/no
effect on CVS complications. PPARα regulates the genes related to the fatty acid
oxidation and maintains energy homeostasis. PPARα agonists reduce the plasma
triglyceride level, increase HDL level, and thus are useful to treat dyslipidemia.
Thus, an agonist on PPARα and PPARγ could be helpful to manage DM,
dyslipidemia, and atherosclerotic disorder. Saroglitazar is a dual PPARα, PPARγ
agonist (predominant PPARα and moderate PPARγ agonist). Saroglitazar, a non-
thiazolidinedione and non- fi brate molecule was approved in India in 2013. The
drug is mainly eliminated through enterohepatic route. Saroglitazar is found to
reduce serum triglycerides, cholesterol, and LDL and improve lipid clearance; the
drug is also helpful to reduce serum glucose level and improve oral glucose
tolerance. During clinical trial pharmacokinetics, safety and tolerability of the drug
are found satisfactory. Average plasma half-life of saroglitazar was 2.9 ± 0.9 h
after single-dose (4 mg) administration. Pyrexia, dyspepsia and gastritis, itching,
abdominal pain, nausea, cough, cold, headache, body pain, and diarrhea are the
common side effects of saroglitazar. The drug is approved in India for the
treatment of diabetic dyslipidemia and to improve glycemic parameters.
Development of a number of other drugs under the category like tesaglitazar,
chiglitazar, sipoglitazar, aleglitazar, and naveglitazar was stopped during clinical or
preclinical trial due to adverse effect, while muraglitazar (another dual agonist) is
withdrawn from the market due to heart failure (Charbonnel 2009; Aggarwal
2014 ; Majumder and Chatterjee 2014 ).

α-Glucosidase Inhibitors
 α-Glucosidase inhibitors such as acarbose, voglibose, and miglitol are the drugs
used to manage DM, but they lack target for a specifi c pathophysiologic aspect of
DM. Acarbose is the fi rst agent

of this class marketed in the 1990s; subsequently, miglitol and voglibose were
discovered. They inhibit small intestinal brush border enzymes competitively
which are playing a key role for breakdown of oligosaccharides and disaccharides
into monosaccharides and thus initiate absorption. Thus, intestinal absorption of
carbohydrates is retarded and moved to more distal portions of the small
intestine and colon. Acarbose restrains both digesting enzyme α-glucosidases and
α-amylase, while voglibose and miglitol don’t have any effect on α-amylase but
inhibit the disaccharide digesting enzymes. These drugs mainly control
postprandial hyperglycemia and help to control both T1DM and T2DM (Reddy et
al. 2000; Cheng and Fantus 2005; Davis 2006 ). A carbose is absorbed poorly or
not absorbed. The drug is metabolized mainly by intestinal bacteria, in an
unchanged form, acarbose is excreted in feces, and some metabolites are
absorbed and excreted through urine. Miglitol is absorbed nicely but doesn’t
produce any systemic effects and is excreted through the kidney in unchanged
form. In comparison to other hypoglycemic agents, these drugs show lesser
hypoglycemic effect and have average HbA1c-lowering effect. Little reduction in
triglyceride concentration and decrease in body weight were observed in patient
receiving α-glucosidase inhibitors. These drugs are used rarely as monotherapy
and not recommended for initial treatment in people suffering from moderate to
severe hyperglycemia. They are administered along with other oral hypoglycemic
agents. α-Glucosidase inhibitors also may produce positive effect by reducing the
risk of CVS complication in diabetic people by reducing fi brinogen levels,
activation of platelet, vascular infl ammation, and improving endothelial function.
GIT disturbances like bloating, discomfort in the abdomen, diarrhea, and fl
atulence are the general side effect. These agents are contraindicated in people
with irritable bowel syndrome or severe dysfunction of the liver and kidney. High
dose of acarbose may alter the concentration of liver enzymes (Cheng and Fantus
2005 ; Krentz and Bailey 2005 ; Richard et al. 2009 ).

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

D PP-4 is an exopeptidase class of proteolytic enzymes present on the different
cell surface including the small intestine, pancreas, kidney, and liver and also
present in plasma as soluble

form. DPP-4 is responsible for degradation of several polypeptides like GLP-1 and
GIP by cleaving the N- or C-terminal amino acid portions from peptides and
proteins. Inhibition of DPP-4 is a key target to treat T2DM, providing enhanced
GLP-1 level, with subsequent rise in insulin secretion and decrease glucagon
secretion, which in turn exerts a benefi cial effect to people suffering from T2DM.
DPP-4 inhibitors represent a new class of drug available for treatment of DM and
its complications. DPP-4 inhibitors presumably increase the serum level of GLP-1
and GIP by averting the degradation of such enzyme, leading to a net
antihyperglycemic effect. Generally, DPP-4 inhibitors have no effect on body
weight. A number of DPP-4 inhibitors like saxagliptin, sitagliptin, and vildagliptin
are available in the market. Table 11.2 includes the details of those drugs. These
drugs not only reduce blood glucose and HbA1c level but may have signifi cant
role in neuropeptide signaling by increasing the action of neuropeptide Y and
growth hormone-releasing hormone. These agents possibly may exert a benefi
cial effect by averting cardiovascular complications in DM. Several studies and
ongoing projects arenb continuing in this area (Badyal and Kaur 2008 ; Seshadri
and Kirubha 2009; Cox et al. 2010 ; Deacon 2011 ; Babu 2012 ; Guedes et al.
2013 ; Mkele 2013 ).

Sodium-Glucose Co-transporter 2 (SGLT) Inhibitor

The kidneys play a major role in the maintenance of glucose levels in the blood
mainly through the reabsorption of glucose by glomerular fi ltration. In normal
condition, almost all fi ltered glucose (approximately 180 g/day) is reabsorbed by
the kidneys and returned to the blood. Less than 1 % of glucose is excreted
through urine after reabsorption. Glucose is a hydrophilic molecule and crosses
the cell membrane through facilitative or active transport mechanism. In
facilitative system, molecule crosses the membrane through concentration
gradient manner, while in active transport system, sodium co-transport system
plays the main role. Sodium-glucose co- transporters (SGLTs) belong to the family
of membrane proteins which are involved in the uptake and transport of glucose
across the brush border membrane of the epithelium of the intestine and
membrane of the proximal tubule of the kidneys. A number of SGLTs exist but
SGLT1 and SGLT2 are the two most studied SGLT. SGLT2 is a low-affi nity but high
ability glucose transporter mostly expressed in the earlier segments (S1) of the
proximal tubule and minimally expressed in other tissues, while SGLT1 is a high-
affi nity, low-capacity glucose transporter present in enterocytes of the small
intestine and in the distal part (S2, S3) of the proximal tubule. SGLT2 is the
principal glucose transported in the kidney and accountable for high glucose
reabsorption (more than 90 %), while SGLT1 absorbs the remainder. After
reabsorption through SGLTs, glucose is reabsorbed, entering in the circulation
through facilitative glucose transporters (GLUTs). In diabetic individual,
hyperglycemia leads to hyperfi ltration, and when the capability

for glucose reabsorption reaches saturation, surplus glucose is excreted through

urine, leading to glucosuria. Genetically inherited SGLT1 mutations cause osmotic
diarrhea, malabsorption, and dehydration, while genetically inherited mutations
of SGLT2 are responsible for renal glucosuria. But glucosuria due to mutation of
SGLT2 is not associated with any alteration of blood glucose level, intravascular
volume, or function of the kidney (Rajesh et al. 2010 ; Tahrani and Barnett 2010 ;
Valentine 2012 ; Fujita and Inagaki 2014 ; Thynne and Doogue

2014 ). Inhibition of SGLT2 and increase in excretion of glucose are a key

therapeutic approach to manage T2DM. SGLT2 inhibitors reduce the level of
blood glucose by inhibiting the reabsorption of fi ltered glucose and may cause
glucosuria. These drugs are also associated with caloric loss, thus reducing body
weight. Activity of SGLT2 inhibitors is not related with the presence of insulin,
magnitude of insulin resistance, or impairment of islet β-cell activity. The
incidence of hypoglycemic effect is also low with SGLT2 inhibitors. These drugs
can be used along with other oral hypoglycemic agents and insulin. But the effi
cacy of these drugs depends on normal glomerular fi ltration mechanism and
quantity of drugs reaching to the proximal tubule. Thus, in moderate to severe
renal impairment condition, SGLT2 inhibitors are ineffective and not
recommended. Though short-term trials showed that SGLT2 inhibitors are not
related with a decline in renal function, concerns have been raised about the
long-term effects of these drugs on inhibition of tubular glucose uptake. SGLT2
inhibitors are responsible for urinary net glucose losses of 20–70 g/day in dose-
dependent manner, though this varies with the degree of hyperglycemia.
Different SGLT2 inhibitors are tabulated in Table 11.3 (Nair et al. 2010 ; Tahrani
and Barnett

2010; Kim and Babu 2012; London New Drugs Group 2012; Donnelly 2013;
Fujita and Inagaki

2014 ; Neumiller 2014 ; Poole and Dungo 2014 ; Poole and Prossler 2014;
Thynne and Doogue

2014 ) (Fig. 11.5 ).