SITAGLIPTIN: AN ORAL ANTI-DIABETIC AGENT

Presented by: Amruta Vaidya

• Introduction to Diabetes Mellitus

• Pharmacological interventions for treatment of diabetes

• Introduction to DPP-IV inhibitors

• Sitagliptin as a DPP-IV inhibitor

• References

CONTENTS

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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

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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

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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)

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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 higherThe 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/Lb) Diabetic: > 7 mmol/L3. Impaired glucose tolerance test (PPG):Administering 75g oral glucose solution and measuring blood sugar after 2 hours.a) Normal: <7.8 mmol/Lb) Diabetic: > 11.1 mmol/L

Diagnostic tests for DM

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

I. Insulin and its analoguesII. Oral hypoglycaemic drugs:1. Sulfonylureas (Insulin secretagogues):a) First generation: Tolbutamide, Chlorpropamideb) Second generation: Glibenclamide, Glipizide, Gliclazide, Glimepiride2. Biguanides: Metformin3. Meglitinides (Insulin secretagogues): Repaglinide, Nateglinide4. Thiazolidinediones: Rosiglitazone, Pioglitazone5. α- Glucosidase inhibitors: Acarbose, MiglitolIII. Bile acid sequestrant: Colesevelam hydrochlorideIV. Amylin Analog: Pramlintide V. GLP-I receptor agonists: Exenatide, LiraglutideVI. DPP-IV inhibitors: Sitagliptin, Vildagliptin, Linagliptin Alogliptin

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DRUG THERAPY FOR T2DM

• 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

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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”.

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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

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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.

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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.

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• 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

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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

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• 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

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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)

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• 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

• 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.

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Safety and tolerability

• 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

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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.

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Clinical efficacy studies of sitagliptin

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.

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• 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

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Emerging treatment guidelines

• 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

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, 11 th edition.8. Basic and Clinical pharmacology-Katzung, B., 12th edition.9. www.diabetes.co.uk 25

REFERENCES