A concise presentation on the DPP-IV inhibitor Sitagliptin an oral anti-diabetic agent. Its general mechanism of action, pharmacokinetics, safety is included.

1. SITAGLIPTIN: AN ORAL ANTI-
DIABETIC AGENT
Presented by: Amruta Vaidya

2. • Introduction to Diabetes Mellitus
• Pharmacological interventions for treatment of diabetes
• Introduction to DPP-IV inhibitors
• Sitagliptin as a DPP-IV inhibitor
• References
CONTENTS
2

3.  Diabetes mellitus is a chronic metabolic disorder characterised
by a high blood glucose concentration-hyperglycaemia caused
by insulin deficiency, often combined with insulin resistance.
 It is characterized by altered metabolism of lipids, carbohydrates
and proteins and an increased risk of complications from
vascular disease.
 DM is associated with absent or inadequate insulin secretion
with or without concurrent impairment of insulin action.
DIABETES MELLITUS
3

4.  Diabetes can be classified into the following general categories:
1. Type 1 diabetes (Insulin dependent DM)(due to β-cell
destruction, usually leading to absolute insulin deficiency)
2.Type2 diabetes (Non-insulin dependent DM) (due to a
progressive insulin secretory defect on the background of insulin
resistance)
3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the
second or third trimester of pregnancy that is not clearly overt
diabetes)
Classification of DM
4

5. 4. Specific types of diabetes due to other causes, diseases of the
exocrine pancreas(such as cystic fibrosis),pancreatectomy, and drug-
or chemical-induced diabetes (such as in the treatment of HIV/AIDS
or after organ transplantation)
5

6. 1. A1C test: The A1C test a common blood test is used to diagnose type
1 and type 2 diabetes. It reflects the average blood sugar level for the
past two to three months. It measures the percentage of haemoglobin
which is glycosylated.
a) Normal: Less than 5.7%
b) Diabetic: 6.5% or higher
The ADA (American Diabetes Association) suggests an A1C of 7%.
2. Impaired fasting glycaemia test (FPG):
Blood sugar levels are taken after 8 hours of fasting.
a) Normal: 4-5.9 mmol/L
b) Diabetic: > 7 mmol/L
3. Impaired glucose tolerance test (PPG):
Administering 75g oral glucose solution and measuring blood sugar after
2 hours.
a) Normal: <7.8 mmol/L
b) Diabetic: > 11.1 mmol/L
Diagnostic tests for DM
6

7. Following are the target blood glucose levels recommended by
NICE (National Institute of Clinical Excellence) in non-diabetics
and Type 2 DM persons:
7

8. I. Insulin and its analogues
II. Oral hypoglycaemic drugs:
1. Sulfonylureas (Insulin secretagogues):
a) First generation: Tolbutamide, Chlorpropamide
b) Second generation: Glibenclamide, Glipizide, Gliclazide,
Glimepiride
2. Biguanides: Metformin
3. Meglitinides (Insulin secretagogues): Repaglinide, Nateglinide
4. Thiazolidinediones: Rosiglitazone, Pioglitazone
5. α- Glucosidase inhibitors: Acarbose, Miglitol
III. Bile acid sequestrant: Colesevelam hydrochloride
IV. Amylin Analog: Pramlintide
V. GLP-I receptor agonists: Exenatide, Liraglutide
VI. DPP-IV inhibitors: Sitagliptin, Vildagliptin, Linagliptin Alogliptin8
DRUG THERAPY FOR T2DM

9. • The first- line anti-diabetic therapies all over the world includes
metformin and sulfonylureas
• Metformin therapy has several advantages like: little or no
hypoglycaemia, low risk of weight gain, improve lipid profile of
diabetics. However, its use is also associated with GI side effects and
lactic acidosis and should not be given in patients with renal and
hepatic disease.
• Sulfonylureas (SU) even though effectively lower plasma glucose
levels, they are associated with variable severities of hypoglycaemia,
weight gain, β- cell death, possible adverse cardiac outcomes.
Need for newer anti-diabetic drugs
9

10. In 2005, the UKPDS (United Kingdom Prospective Diabetes Study)
showed for the first time that the combination of SU and metformin
resulted in a progressive decline in β- cell function and by 3 years up
to 50% of diabetic patients can require an additional pharmacological
agent to maintain the glycosylated haemoglobin (HbA1c) <7.0%.
Also, based on data from the UKPDS between 75% and 80% of β- cell
function is lost once hyperglycaemia fulfilling the definition of
diabetes mellitus develops. After 10–15 years of diabetes duration
<10% of endogenous insulin is present and exogenous insulin therapy
becomes necessary.
Hence, “it has become necessary to shift to newer therapies that can
help conserve β- cell function”.
10

11. DPP-IV inhibitors or Gliptins came into picture when it was discovered that these
compounds could modulate a physiological mechanism in the body.
There are certain peptides which are normally released from endocrine cells in the
small intestinal mucosa in response to food to enhance meal-induced insulin
secretion, and also to modulate glucagon lowering in fed state. These are called
incretin hormones.
In humans, the two main physiologically important incretin hormones are: (1) GLP-
1 (Glucagon like peptide) and (2) GIP (Glucose dependent insulinotropic
polypeptide).
In patients with type 2 DM, postprandial GLP-1 secretion is modestly impaired but
GLP-1 actions are preserved. While, GIP secretion is normal in type 2 diabetics,
these individuals are relatively resistant to the acute insulinotropic effect of
exogenous GIP administration.
DPP-IV INHIBITORS/ GLIPTINS
11

12. In diabetics, GLP-I plays a significant role:
a) Augments glucose-dependent insulin secretion.
b) Lowers glucagon secretion and thereby reduces post-prandial and fasting
hyperglycaemia.
c) Improves insulin sensitivity and enhances glucose disposal
c) Reduces gastric emptying and thus induces satiety.
d) Stimulates insulin biosynthesis.
In vitro studies and animal studies have revealed that both GLP-I and GIP promote
pancreatic β cell growth and survival.
However, these peptides are rapidly inactivated by dipeptidyl peptidase IV enzyme.
Hence, DPP-IV inhibitors were proposed to explore the potential of incretin hormones.
12

13. List of available and expected DPP-IV inhibitors are:
1. Sitagliptin (Merck Sharp and Dohme Corp, approved as Januvia
by US FDA in year 2006)
2. Vildagliptin (Novartis, approved as Galvus by EU in year 2007)
3. Saxagliptin (Bristol-Myers Squibb, approved as Onglyza by US
FDA in 2010)
4. Linagliptin (Boerhinger Ingelheim, approved as Tradjenta by US
FDA in year 2011)
5. Alogliptin (developed by Takeda Pharmaceutical Company
Limited, approved for use in Japan)
6. Dutogliptin (being developed by Phenomix Corporation)
7. Gemigliptin (being developed by LG Life Sciences)
Sitagliptin, Vidagliptin, Saxagliptin are approved for use in India.
13

14. • Sitagliptin was the first DPP-IV inhibitor approved by the US FDA in
2006.
• It was launched by Merck Sharp and Dohme (MSD) as Januvia.
• Sitagliptin produces sustained inhibition of DPP-4 and is indicated for
the treatment of type 2 DM to improve glycaemic control in
combination with metformin or a thiazolidinedione (TZD), when diet
and exercise, plus metformin or a TZD do not provide adequate
glycaemic control.
Available brands of Sitagliptin in India:
1. Januvia, Janumet (MSD)
2. Istamet, Istavel [Sun pharma (Arian)]
3. Sitar-M [Olcare (Cardium)]
4. Zita-Met (Glenmark)
SITAGLIPTIN
14

15. Status of Sitagliptin in Pharmacopoeias
IP USP BP Eu Ph.
1.Sitagliptin
tablets
2.Sitagliptin
phosphate
1. Sitagliptin +
Simvastatin
tablets
2. Sitagliptin
phosphate
Sitagliptin
phosphate
Sitagliptin
tablets
15

16. • Sitagliptin is a highly selective DPP-IV inhibitor compared to other
gliptins.
• It is an orally active inhibitor of DPP-IV which prevents degradation
of endogenous GLP-I and other incretins, potentiating their action
resulting in limitation of postprandial hyperglycaemia.
• The recommended dose is 100 mg once a day with or without food.
• Sitagliptin reduces HbA1c level approximately by 0.7% and is
similarly effective when combined with metformin or pioglitazone.
• An Asian study (China India Korea study) suggested that sitagliptin
was more effective in the Indian population with greater HbA1c
reductions of approximately 1.3% compared to placebo.
Mechanism of action of sitagliptin
16

17. Pharmacokinetics of Sitagliptin
Parameter Value
Bioavailability >85%,
Half-life approximately 12 hours
Absorption 1–4 hours
Distribution 38% protein bound
Metabolism Not appreciably metabolized
Elimination Renal (80% unchanged)
17

18. • Since, Sitagliptin is eliminated renally, dose adjustment is necessary in case of
renal insufficency.
• a) Moderate renal insufficiency: 50mg/day
• b) Severe/End stage renal insufficiency: 25 mg/day
• Administration of Sitagliptin with other drugs including metformin, pioglitazone,
glyburide, rosiglitazone, simvastatin revealed no interactions.
• However, its concurrent use may increase serum levels of digoxin.
• Sitagliptin is a pregnancy risk category B agent and should be used during
pregnancy if deemed necessary. Caution is also advised in women who are nursing.
• It is currently unknown whether sitagliptin is secreted in human breast milk, and the
effects on nursing babies are also unknown. Safety and efficacy in patients <18 y of
age have not been studied.
18

19. • Low risk of hypoglycaemia
• Weight neutral agent.
• Adverse effects which includes nausea, constipation, diarrhoea,
nasopharyngitis are mild and transient.
• However, serious hypersensitivity reactions have been reported in
patients treated with sitagliptin which includes anaphylaxis,
angioedema and exfoliative skin conditions. Hence, it is contradicted
in persons who have had a serious hypersensitivity reaction to it.
19
Safety and tolerability

20. • Good tolerability profile with low incidence of adverse
events.
• Effect of incretin hormones (GLP-I, GIP) on insulin synthesis
and release is glucose-dependent, hence pose a very low risk
of hypoglycaemia compared to sulfonylureas, meglitinides,
insulin.
• No weight gain.
Advantages of Sitagliptin over Other Agents
used To Treat T2DM
20

21.  Double blind placebo controlled studies have been done to establish
clinical efficacy of sitagliptin as monotherapy and combination
therapy.
1. Monotherapy:
Sitagliptin significantly improved HbA1C, FPG, PPG levels compared
with placebo. It is found to be equally efficacious when compared to
metformin, SU, thiazolidinediones.
Sitagliptin monotherapy requires intact β cells , hence it maybe best
used in people with early-stage diabetes.
2. With Metformin:
This combination was found to be significant than the placebo.
Sitagliptin plus metformin was well tolerated and had a lower risk of
hypoglycaemia than glipizide with metformin.
This combination can benefit T2DM patients by enhancing the incretin
axis.
21
Clinical efficacy studies of sitagliptin

22. 3. With pioglitazone:
Sitagliptin with pioglitazone significantly improved HbA1C and FPG
compared to placebo plus pioglitazone.
4. With glimepiride:
Sitagliptin plus glimepiride with or without metformin significantly
improved HbA1C and FPG compared to placebo plus glimepiride.
However, with Sitagliptin plus glimepiride with or without
metformin combination incidence of hypoglycaemia was higher and
there was weight gain of 1.1 kg compared with placebo plus
glimepiride combination.
Hence, for combination of sitagliptin with a sulfonylurea, lower dose
of SU may be required to reduce risk of hypoglycaemia.
22

23. • The American Diabetes Association (ADA), American
Association of Clinical Endocrinologists (AACE), European
Society, and NICE (UK) guidelines approve sitagliptin as
monotherapy and add-on therapy with metformin,
thiazolidinediones especially if the patient is experiencing an
increased incidence of hypoglycemia and/or weight gain.
• However, Sitagliptin is not approved for use in patients with type
1 diabetes or to treat diabetic ketoacidosis
23
Emerging treatment guidelines

24. • Even though Sitagliptin is an expensive drug, the major advantage of
this drug is, it has a low risk of producing hypoglycaemia, is a weight
neutral agent and also helps to improve the lipid profile in patients.
• Although it remains to be demonstrated in humans, the potential β cell
protective effect of Sitagliptin and other DPP-IV inhibitors could be
ideal for the prevention of Type 2 DM.
• Sitagliptin can be beneficial in preventing diabetes in those with pre-
diabetes. As these patients have adequate β cell mass, they may benefit
most from this agent.
24
CONCLUDING THOUGHTS

25. 1.Seshadri, K.; Kirubha, M., Gliptins: A new class of oral antidiabetic
agents. Indian journal of pharmaceutical sciences 2009, 71 (6), 608.
2.Bardsley, J. K.; Ratner, R. E., Sitagliptin: an oral agent for glucose
control. 2008.
2.Gupta, V.; Kalra, S., Choosing a gliptin. Indian journal of
endocrinology and metabolism 2011, 15 (4), 298.
3. Mukherjee, A. K., Evolution of Gliptins Over the Last 5 Years.
4.Midlands Therapeutics Review and Advisory Committee,
Commissioning support, DPP-4 inhibitors (Gliptins), 2014.
5.American Diabetes Association: Standards of Medical Care in
Diabetes, Diabetes Care, 2015, 38, 1-94.
6. Rang and Dale’s Pharmacology, 7th edition.
7. Goodman and Gillman-The pharmacological basis of therapeutics,
11th edition.
8. Basic and Clinical pharmacology-Katzung, B., 12th edition.
9. www.diabetes.co.uk 25
REFERENCES