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Review Article

Oral Antidiabetic Agents: Recently Available Novel Oral

Antidiabetic Agents in India: A Clinical Review
Nitin Kapoor1,2, Nihal Thomas1
1
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India, 2Non communicable Diseases Unit, Melbourne School
of Population and Global Health, University of Melbourne, Melbourne, Australia

Abstract
Oral anti-diabetic agents form an important therapeutic strategy in the management of diabetes, after lifestyle modification. There are several new
agents available, like dipeptidyl peptidase 4 (DPP4) inhibitors and sodium- glucose cotransporter 2 (SGLT2) inhibitors have been approved for use as
monotherapy when diet and exercise are inadequate and when metformin is not tolerated, and can also be utilized as an add on to other glucose-lowering
agents, including insulin. The therapeutic, pharmacokinetic and safety profiles of these agents are different from the older agents. Hydroxychloroquine
(hcq) and bromocriptine have been recently cleared for use and show beneficial effects in control of blood glucose and HbA1C levels.

Key words: Dipeptidyl peptidase 4 inhibitors, glibenclamide, gliclazide, oral antidiabetic agents, pioglitazone

Address for correspondence: Dr. Nitin Kapoor, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore ‑ 632 004,
Tamil Nadu, India. E‑Mail: nitin.endocrine@gmail.com

Introduction
The mainstay of treatment of patients with type 2 diabetes includes modifications in lifestyle (diet and exercise), oral antidiabetic
agents, and insulin therapy. The major aims are not only to improve glycemic control, reduce weight, and improve the quality of
life of these patients but also to reduce the long‑term risk of cardiovascular disease by ensuring compliance to their medicines and
minimizing adverse effects. The specific medications used in patients with type 2 diabetes are determined by clinical judgment
about the likely balance between beta cell impairment and insulin resistance. Preventing hypoglycemia and improving compliance
through less frequent dosing are the other important targets. The variety of available medications has expanded greatly over the
last decade, and even more are in the pipeline, this is especially because there is a greater understanding of the pathogenesis now
and of type 2 diabetes mellitus (T2DM) and at least eight organs are implicated in its pathogenesis [Figure 1].1,2 In this review,
the authors discuss the latest recommendations in initiating oral antidiabetic agents (OADs) in diabetes and have summarized
the current understanding and available literature on the recently available novel oral antidiabetic agents in India.

Role of Oral Antidiabetic Agent Therapy in Type 2 Diabetes Mellitus

Oral antidiabetic agents follow diet and exercise in the management of an individual with T2DM. While trying to use OADs in
the control of diabetes mellitus, one should also attempt to:
• Conserve islet cell function and thereby delay subsequent use of insulin
• Decrease the prevalence of hypoglycemic episodes
• Improve patient compliance with medications (attempting to reduce the frequency of dosing)

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DOI: How to cite this article: Kapoor N, Thomas N. Oral antidiabetic agents:
10.4103/cmi.cmi_39_17 Recently available novel oral antidiabetic agents in India: A clinical review.
Curr Med Issues 2017;15:169-76.

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Kapoor and Thomas: Oral antidiabetic agents in India

• Consider the cost factor and affordability of the patient of type 2 diabetes. A long‑term use of metformin may
• To prevent weight gain. be associated with biochemical Vitamin B12 deficiency,
and periodic measurement of Vitamin B12 levels should
The mechanism of actions of various classes of OADs
be considered in metformin‑treated patients, especially
is summarized in Figure 2, and a comparative summary
in those with anemia or peripheral neuropathy (B)*
of the existing oral antidiabetic agents is presented in
• Consider initiating insulin therapy  (with or without
Figure 3 and Table 1.
additional agents) in patients with newly diagnosed type 2
diabetes who are symptomatic and/or have A1C  ≥10%
Guidelines for Initiating Oral Antidiabetic (86 mmol/mol) and/or blood glucose levels ≥300 mg/dL
Agents in an Individual Diagnosed with Diabetes (16.7 mmol/L) (E)*
• If noninsulin monotherapy at maximum tolerated
These guidelines [Figure 4] are based on the new American
dose does not achieve or maintain the A1C target after
Diabetes Association (ADA 2017) recommendations. Some
3 months, add a second oral agent, a glucagon‑like peptide
excerpts from the ADA 2017 guidelines are given below.3
1 (GLP1) receptor agonist, or basal insulin (A)*
Recommendations • A patient‑centered approach should be used to guide the
• The first choice of management in a person newly choice of pharmacologic agents. Considerations include
diagnosed with diabetes is always calculated diabetic efficacy, hypoglycemia risk, impact on weight, potential
diet and exercise [Table 2]3 side effects, cost, and patient preferences (E)*
• Metformin, if not contraindicated and if tolerated, is the • For patients with type 2 diabetes who are not achieving
preferred initial pharmacologic agent for the treatment glycemic goals, insulin therapy should not be delayed (B)*

Figure 1: Diabetes pathophysiology: Traditional triad to ominous octet.

Figure 2: Mechanism of action of obstructive airway diseases.

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Kapoor and Thomas: Oral antidiabetic agents in India

Figure 3: Comparison of the oral antidiabetic agents available for diabetes.

• In patients with long‑standing suboptimally controlled

Table 1: Clinical markers to determine the choice of
type 2 diabetes and established atherosclerotic
obstructive airway disease’s
cardiovascular disease, empagliflozin, or liraglutide
Determinants First choice OAD OAD to be should be considered as they have been shown to reduce
avoided cardiovascular and all‑cause mortality when added to
Overweight/Obese Metformin Glibenclamide standard care. Ongoing studies are investigating the
Body mass index (BMI) DPP4 inhibitors Glipizine cardiovascular benefits of other agents in these drug
>25 kg/m2, SGLT2 inhibitors Thiazolidinediones classes (B)*.
waist hip ratio: Male
>0.9, Female >0.85 (*Levels of evidence: A ‑ Clear evidence from well‑conducted,
generalizable randomized controlled trials [RCTs] that
Presence of GI Sulfonylurea Acarbose are adequately powered, B ‑ supportive evidence from
symptoms thiazolidinediones DPP4 inhibitors well‑conducted cohort studies, C ‑ supportive evidence from
Renal dysfunction Repaglinide Metformin poorly controlled or uncontrolled studies, E ‑ expert consensus
DPP4 inhibitors or clinical experience).

Economic constraints Sulfonylurea Relative to the

metformin company and
Recently Available Novel Oral Antidiabetic
agent used Agents in India
Complications of Insulin should be Dipeptidyl peptidase 4 inhibitors
diabetes used in severe The currently available dipeptidyl peptidase 4 (DPP4)
or progressive inhibitors in India (sitagliptin, vildagliptin, saxagliptin,
painful linagliptin, and teneligliptin) are approved to be used as
neuropathy/ monotherapy or combination with other antidiabetic agents.4
proliferative
In addition, once‑weekly DPP4 inhibitors (omarigliptin and
retinopathy/
maculopathy
trelagliptin) are licensed in Japan and may reach the Indian
market soon.5,6
Source: ADA 2007 guidelines, SGLT2: Sodium glucose
cotransporter 2, DPP‑IV: Dipeptidyl peptidase 4 inhibitors, Mechanism of action
GI: Gastrointestinal, OAD: Obstructive airway disease, BMI: Body The mechanism of action of DPP4 inhibitors is by elevating
mass index, ADA: American Diabetes Association the circulating levels of incretin hormones, notably GLP1 and

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Kapoor and Thomas: Oral antidiabetic agents in India

Figure 4: Guidelines for initiating oral antidiabetic agents in a newly diagnosed patient with diabetes.

gastric inhibitory polypeptide (GIP). This helps to improve increased by sitagliptin, thereby increasing and prolonging the
the defective nutrient response in secretion of incretins by the action of these hormones, which ultimately leads to lowering of
intestine. In addition to its incretin effect, GIP also reduces blood glucose both in fasting and postprandial state. Sitagliptin
gastric acid secretion and has a role in adipogenesis and has been reported to have minimal hypoglycemic events
possibly β‑cell proliferation.7 In addition, GLP1 causes a and reduced weight gain when compared to sulfonylureas.
reduction in glucagon secretion and has extrapancreatic actions Sitagliptin can also be combined with insulin to reduce the
that enhance satiety and delay gastric emptying. dose requirement.
Commonly available dipeptidyl peptidase 4 inhibitors Dosing
Sitagliptin Initially as 100 mg once daily with or without food. If
Sitagliptin, the first approved DPP‑IV inhibitor exerts its creatinine clearance is 30–50 mL/min/1.73 m2, reduce dosage
antihyperglycemic effect by slowing the inactivation of incretin to 50 mg daily. If creatinine clearance is <30 mL/min/1.73 m2,
hormones. Concentrations of intact incretin hormones are reduce dosage to 25 mg daily.

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Kapoor and Thomas: Oral antidiabetic agents in India

decrease the efficacy of linagliptin. Therefore, patients

Table 2: Exercise recommendations in diabetes (American
requiring such drugs should receive an alternative to linagliptin.
Diabetes Association 2017)
Age group Exercise recommendation Teneligliptin
Children and adolescents 60 min/day or more of moderate or
The usual dose of teneligliptin is 20 mg once daily. It is
with type 1 or type 2 vigorous intensity aerobic activity, a cheaper DPP4 inhibitor available in Japan, Korea and
diabetes or prediabetes with vigorous muscle strengthening India. Its pharmacological profile is similar to other DPP4
and bone‑strengthening activities at inhibitors. No dose adjustment is required in patients with
least 3 days/week renal dysfunction. However, caution needs to be exercised
Most adults with type 1C 150 min or more of moderate to when prescribing teneligliptin to patients who are prone to
and type 2B diabetes vigorous QT prolongation.
Intensity physical activity per week,
spread over at least 3 days/week, Cardiovascular safety and adverse effects
with no more than 2 consecutive DPP4 inhibitors are usually well tolerated, and the incidence
days without activity of adverse effects is often similar to placebo and much
2-3 sessions/week of resistance lower than other glucose‑lowering agents.8 The incidence of
exercise on nonconsecutive days gastrointestinal symptoms, which is the most common side
Decrease the amount of time effect, is lower with DPP4 inhibitors than with metformin or a
spent in daily sedentary behavior. GLP1RA.8 The chance of hypoglycemia in subjects receiving
Prolonged sitting should be DPP4 inhibitor is very low except when used in combination
interrupted every 30 min for blood
with sulfonylureas or insulin.9
glucose benefits, particularly in
type 2 diabetes Several meta‑analyses and pooled analyses have shown that
Flexibility training and balance DPP4 inhibitors (individually and as a class) are associated
training are recommended with reductions in cardiovascular events.10 However, most
2-3 times/week for older adults of these studies were retrospective and not specifically
with diabetes to increase flexibility,
designed to examine the effect of DPP4 inhibitors on the
muscular strength, and balance
incidence of cardiovascular disease. The results of three
RCTs (SAVOR–TIMI, EXAMINE, and TECOS) demonstrated
Adverse effects that saxagliptin, alogliptin, and sitagliptin are not associated
Mild gastrointestinal symptoms such as nausea, vomiting, with an increased risk of adverse cardiovascular outcomes.11‑13
diarrhea, and abdominal pain have been reported, but are not
The individual results of the SAVOR–TIMI, EXAMINE, and
clinically significant. There is a small increased risk of upper
TECOS trials did not show any increased risk of pancreatitis
respiratory tract infection, urinary tract infection (UTI), and
or pancreatic cancer, but a meta‑analysis of these RCTs did
headache but the prevalence of these infections appear to be
demonstrate a significantly increased risk of acute pancreatitis
less according to a recent Cochrane review. Sitagliptin is also
in patients using DPP4 inhibitors compared with those
rarely associated with skin reactions which may rarely include
receiving standard care  (odds ratio: 1.82, 95% confidence
Stevens–Johnson syndrome.
interval [CI]: 1.17–2.82, P = 0.008).11‑13
Vildagliptin
This agent has to be administered at a dosage of 50 mg
Comparisons of existing dipeptidyl peptidase 4 inhibitors
Sitagliptin has been compared to saxagliptin and vildagliptin
twice a day. It has not been approved by the Food and Drug
in two randomized control trials. Though in both comparisons,
Administration (FDA) for usage in renal failure. However, it has
the drugs performed almost at par with each other, sitagliptin
been approved by FDA for use as a combination with insulin. It
resulted in slightly lower fasting blood glucose than saxagliptin
reduces postprandial lipemia and has a favorable effect on the blood
(treatment difference 5 mg/dl, 95% CI: 1.3–8.8 mgl/dl).14,15 An
pressure. It is not recommended for use in moderate renal failure.
ongoing study (CAROLINA80) has been designed to examine
Saxagliptin the effect of linagliptin on cardiovascular outcomes with an
The usual dose of saxagliptin is 2.5 mg or 5 mg once daily, active comparator (glimepiride) rather than placebo.
with the 2.5 mg dose recommended for patients with moderate
to severe chronic kidney disease  (glomerular filtration rate Sodium‑glucose Cotransporter 2 Inhibitors
[GFR] ≤50 mL/min) and for patients taking strong cytochrome
The currently available sodium‑glucose cotransporter
P450 3A4/5 inhibitors (e.g., ketoconazole).
2  (SGLT2) inhibitors include dapagliflozin, canagliflozin,
Linagliptin and empagliflozin. They have been approved for use as
The usual dose of linagliptin is 5 mg once daily. No dose monotherapy when diet and exercise are inadequate and when
adjustment is needed in patients with renal or hepatic metformin is not tolerated, and can also be utilized as an add‑on
impairment. Inducers of CYP3A4 (e.g., rifampicin) may to other glucose‑lowering agents, including insulin.16

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Mechanism of action In light of the recently published CANVAS trial in June 2017,
The concept behind the action of these drugs is based on the it suggested that canaglifozin significantly reduced composite
fact that each day, approximately 180 g of glucose is filtered outcome of death from cardiovascular causes, nonfatal
daily from the glomeruli of a normal adult individual, and myocardial infarction, or nonfatal stroke than placebo (occurring
almost all of it is reabsorbed from the glomerular filtrate and in 26.9 vs. 31.5 participants per 1000 patient‑years; hazard
returned to the circulation. This co‑transport of glucose along ratio, 0.86; 95% CI: 0.75–0.97; P < 0.001 for noninferiority;
with sodium is brought about by the active transport of sodium P = 0.02 for superiority). However, it was also associated with
out of the basolateral cells by the Na/K‑ATPase pump. Glucose an increased risk of amputation (6.3 vs. 3.4 participants per
is also shifted out of the cell with the concentration gradient and 1000 patient‑years; hazard ratio, 1.97; 95% CI: 1.41–2.75);
subsequently returned to the bloodstream by glucose transporters. amputations were primarily at the level of the toe or metatarsal.
It is not yet clear if this risk is a class effect or specific to this
Sodium glucose transporters (SGLTs) in the gut and kidneys
drug.
transfer glucose into enterocytes or ductal epithelial cells across
the luminal membrane. The main types of SGLTs are SGLT1 Empagliflozin
and SGLT2, which are essentially responsible for intestinal The reductions in HbA1c, body weight, and systolic blood
glucose absorption and for reabsorption of the filtered glucose pressure using empaglifozin were to the scale of 0.7%–0.8%,
in the renal tubules, respectively.17,18 SGLT2 has a low‑affinity 1.5–2.5 kg, and 2.9–4.1 mmHg respectively, and this has been
but a high‑capacity for glucose transport in the S1 segment of shown to be maintained in trial extensions up to 76 weeks.26‑29
the proximal tubules, which is suited for reabsorption of a large Empagliflozin has also been well tolerated and efficacious in
load of filtered glucose that enter the tubules. SGLT1, which is patients with estimated GFR 30–60 ml/min/1.73 m2 over a
also present in the kidneys, has a high‑affinity but low‑capacity 24‑week trial.30
of glucose transport that is best suited to reabsorb of glucose at
lower concentrations in the S3 segment of proximal tubules.18,19 All the three drugs have also shown modest reductions in
blood pressure as well.
In T2DM, renal glucose handling and transport is increased,
likely due to the upregulation of SGLT2. Inhibition of this Safety and adverse effects
reduces reabsorption of filtered glucose and therefore lowers the SGLT2 inhibitors are usually associated with a low risk of
blood glucose concentration by enhancing glucose excretion. hypoglycemia except when used in combination with insulin
or sulfonylureas.16 SGLT2 inhibitors have also been associated
Competitively inhibition of SGLT2 can potentially eliminate with an increased risk of genitourinary tract infections, but this
60–90 g of glucose per day. 20 The effects of SGLT2 increase in UTI has not been consistently reported.16 The risk
inhibition is self‑limiting, dependent on renal functions and is shown to be greater in women than men, and none of the
noninsulin‑dependent.20 SGLT2 inhibition and the resultant reported infections was severe.24
glycosuria results in mild diuresis and calorie loss with
corresponding reductions in blood pressure and weight.21 SGLT2 inhibitors are also associated with small increases in
low‑density lipoprotein (LDL) and high‑density lipoprotein
Commonly available sodium glucose transporter (HDL) cholesterol, these effects are more than what was
2 inhibitors observed with canagliflozin, and long‑term consequences of
Dapagliflozin these are yet to be determined.24
When used in doses of 5 or 10  mg per day, dapagliflozin
SGLT2 inhibitors, particularly canagliflozin, might have
has been showed to reduce glycated hemoglobin (HbA1c)
adverse effects on the risk of developing osteoporotic fractures.
by 0.8%–0.9% and also has shown to reduce body weight
A subset analysis of the results from the CANVAS trial
by 2.8–3.2 kg.22 It has also improved glycemic control and
(n  =  4,327) showed a significant increase in fractures with
achieved weight reduction when used as an add‑on therapy
canagliflozin  (4.0%) compared with placebo  (2.6%; heart
with other oral glucose lowering agents.23 It is available as
rate [HR]: 1.51, 95% CI: 1.04–2.19).31
5 mg/10 mg tablets and is prescribed as a once‑daily dose.
Several case reports of euglycemic and hyperglycemic diabetic
Canagliflozin
ketoacidosis have been reported in patients who received
Canagliflozin showed similar effects in weight and HbA1c
SGLT2 inhibitors.32,33 However, many of the reported patients
reduction when used as monotherapy (HbA1c ‑ 1.08%) or as
had ketosis either due to a breach in insulin therapy, intercurrent
add‑on treatment to other oral antidiabetic agents (0.73%)24 The
illness, or off‑label usage of these drugs. Patients treated with
addition of canagliflozin to insulin treatment has also shown to
insulin should, therefore, be educated not to discontinue insulin
result in a significant reduction in HbA1c up to a duration of
when they observe a reduction in blood glucose levels after the
52 weeks.25 Canagliflozin became the first SGLT2 inhibitor to
introduction of an SGLT2 inhibitor. These drugs are currently
be approved by the FDA in 2013. It is currently indicated as an
not approved in patients with type 1 diabetes mellitus.
adjunct to diet and exercise in adults with T2DM. Canagliflozin
is available as 100 mg/300 mg tablets and is prescribed as a There has also been a recent interest in the cardiovascular
once‑daily dose. protection offered by these drugs the mechanisms behind

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Kapoor and Thomas: Oral antidiabetic agents in India

which are still to be elucidated. In a study of 7020 patients which if given in the morning would reset the abnormally
with high‑risk T2DM, the occurrence of a composite end point elevated sympathetic drive in the hypothalamus in patients
of nonfatal myocardial infarction, nonfatal stroke, and death with T2DM. This in turn would result in reducing the hepatic
from cardiovascular causes was lower with empagliflozin than glucose output. It has also shown not only to augment the
placebo, in addition to standard therapy (HR: 0.86, 95% CI: release of insulin but also to increase its sensitivity in the
0.74–0.99, P = 0.04 for superiority).34 Empagliflozin treatment peripheral tissues. The addition of bromocriptine to poorly
also significantly reduced the risk of cardiovascular death, controlled type 2 diabetic patients treated with diet alone,
death from any cause, and hospitalization from heart failure.34 metformin, sulfonylureas, or thiazolidinediones produces a
Subgroup analyses revealed that the benefits of empagliflozin 0.5–0.7 decrement in HbA1c.
were more evident in the Asian population, in patients with
The doses used to treat diabetes (up to 4.8 mg daily) are much
body mass index <30 kg/m2 and HbA1c <8.5%, in those not
lower than those used to treat Parkinson’s disease, and apart
on insulin treatment and in those with diabetic nephropathy.
from nausea, the drug is well‑tolerated. The novel mechanism
Hydroxychloroquine in diabetes of action, good side effect profile, and its effects to reduce
Antimalarial drugs are well‑tolerated and safely used cardiovascular event rates make it an attractive option for the
therapeutic agents that are commonly utilized for disorders treatment of type 2 diabetes.36
such as rheumatoid arthritis and systemic lupus erythematosis.
Financial support and sponsorship
Their benefit for glycemic control has been observed in patients
Nil.
on these drugs for immunological disorders. Hypoglycemia is
one of the unusual adverse effects of these groups of drugs. Conflicts of interest
Hydroxychloroquine (HCQ), in particular, was shown to be There are no conflicts of interest.
effective in lowering the HbA1c in sulfonylurea refractory
patients. The addition HCQ to insulin therapy causes a References
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176 Current Medical Issues  ¦  Volume 15  ¦  Issue 3  ¦  July‑September 2017