Incretins in Diabetes Mellitus

Dr. Abhijit Chowdhury

Honorary Medical Officer; Unit: 1

Department of Endocrinology

BIRDEM

Incretins

• These are hormones produced by GIT in

response to incoming nutrients, and have

important actions that contribute to glucose

homeostasis.

• Two hormones-

▫ Gastric inhibitory polypeptide (GIP)

▫ Glucagon like peptide-1 (GLP-1)

• In 1902, William Bayliss and Starling postulated

that a gut factor(s) might act on the endocrine

pancreas in response to oral nutrients.

• In 1930, La Barre described a greater effect of

oral rather parenteral glucose in increasing

insulin secretion.

• La Barre and Still coined the term Incretin to

describe the hormonal activity released from the

intestine that stimulates insulin secretion.

GIP (Gastric Inhibitory Polypeptide)

• Also known as Glucose-dependent Insulinotrophic Peptide.

• 42 aa polypeptide; discovered in 1969.

• Secreted from proximal intestinal K cells (Duodenum and Jejunum).

• Released by ingestion of carbohydrates and fats.

• Stimulates insulin release.

• Inhibits gastric acid secretion.

• Type 2 diabetes patients are resistant to the action of GIP, hence high blood level of GIP is found in these patients.

GLP-1 (Glucagon Like Peptide-1)

• 30 aa polypeptide; discovered in 1988.

• t ½: 1 to 2 minutes.

• Secreted from distal intestinal L cells.

• Released by ingestion of carbohydrates and rapid release occurs from ileal L cells within 15 minutes of eating.

• Releases insulin if BG is >70- 90 mg/dL.

• In Type 2 diabetes patients there is deficiency of GLP-1.

Pancreatic Islet Cells are Targets for Incretin Hormones

GLP-1=Glucagon-Like Peptide-1

Adapted from Drucker D. Diabetes Care. 2003;26:2929-2940. Wang Q, et al. Diabetologia. 2004;47:478-487.

Incretin Response

Food

intake

α-Cellβ-Cell

Pancreatic Islet

cells

Incretin

• Incretin hormones increase insulin gene transcription, leads to β cell proliferation, and β cell apoptosis. As a whole there is increased insulin secretion.

• Incretins slow down gastric emptying and suppress appettite.

• Incretins are rapidly inactivated by the Dipeptidyl peptidase-4 (DPP-4) enzyme.

Effects of GLP-1 and GIP on Glucose

Metabolism

GLP-1 GIP

Insulin secretion insulin secretion

cell mass cell mass

glucagon secretion and

hepatic gluconeo-genesis

glucagon secretion but

gluconeogenic response to glucagon

gastric emptying gastric emptying

The Ominous Octet

Islet -cell

Impaired

Insulin Secretion

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

IncreasedLipolysis

Increased Glucose

Reabsorption

Increased

HGP

DecreasedIncretin Effect

Decreased pancreatic insulin secretion

Peripheral

insulin

resistance in

muscle and fat

tissue

Increased

hepatic

glucose output

Deficient

incretin

hormones

The Incretin Effect Is Diminished in Subjects

With Type 2 Diabetes

Oral glucose load Intravenous (IV) glucose infusion

Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag.

Time, min

Control Subjects (n=8)

IR I

ns

uli

n,

mU

/L

80

60

40

20

0

18060 1200

Normal Incretin Effect80

60

40

20

0

18060 1200

Subjects With Type 2 Diabetes (n=14)

Diminished Incretin Effect

Time, min

IR I

ns

uli

n,

mU

/L

Treatment options

• Incretin mimetics which are Glucagon-like

peptide-1 (GLP-1) agonists.

• Dipeptidyl peptidase-4 (DPP-4) enzyme

inhibitors which inhibit the breakdown of GLP-1.

DPP-4 inhibitors or Incretin

Enhancers• Sitagliptin (2006)

• Saxagliptin(2009)

• Vildagliptin

• Linagliptin(2011)

• Alogliptin (2013)

Incretin Mimetics/GLP-1 agonists or

analogs• Exenatide (2005)

• Liraglutide (2010)

DPP-4 inhibitors

• Indicated as an adjunct to diet and exercise to

improve glycemic control in adults with type 2

diabetes mellitus.

• Limitations of Use-

▫ Should not be used in patients with type 1

diabetes or for the treatment of diabetic

ketoacidosis.

▫ Has not been studied in patients with a history of

pancreatitis.

• Can be taken with or without food.

• Contraindicated if history of serious

hypersensitivity reaction to the drug.

• Safety and effectiveness in children under 18

years have not been established.

• There are no adequate and well-controlled

studies in pregnant women.

Inhibition of DPP-4 increases active GLP-1

GLP-1inactive

(>80% of pool)

ActiveGLP-1

Meal

DPP-4

IntestinalGLP-1 release

GLP-1 t½=1–2 min

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1Adapted from Rothenberg P, et al. Diabetes 2000; 49 (suppl 1): A39. Abstract 160-OR.Adapted from Deacon CF, et al. Diabetes 1995; 44: 1126-1131.

Potential cardiovascular benefits of

DPP-4 inhibitors

• Neutral effect on body weight.

• Improved glycemic control, including PPG

reduction.

• Decreased systolic blood pressure.

• Improved lipid profile.

• Reduction in C-reactive protein (CRP).

• Improvement of endothelial dysfunction.

Sitagliptin

• Dosage and administration-

▫ The recommended dose is 100 mg once daily.

▫ Can be taken with or without food

▫ Maximum dose 100 mg daily.

Dosage Adjustment in Patients With Moderate, Severe

and End Stage Renal Disease (ESRD)

Moderate Severe and ESRD

50 mg once daily 25 mg once daily

(CCr >30 to <50 mL/min

~Serum Cr levels [mg/dL]

Men: >1.7– ≤3.0;

Women: >1.5– ≤2.5)

(CCr <30 mL/min

~Serum Cr levels [mg/dL]

Men: >3.0;

Women: >2.5;

or on dialysis)

Adverse reactions

• Upper respiratory tract infection

• Nasopharyngitis

• Headache

PRECAUTIONS

• Postmarketing reports of acute pancreatitis,

including fatal and non-fatal hemorrhagic or

necrotizing pancreatitis.

• Postmarketing reports of acute renal failure,

sometimes requiring dialysis.

• Increased risk of hypoglycemia when added to

an insulin secretagogue or insulin therapy.

Vildagliptin

• Indications

▫ In dual combination with metformin or sulfonylurea

or pioglitazone.

▫ In triple combination with a sulfonylurea and

metformin.

▫ In combination with insulin (with or without

metformin).

Dosage and administration

• Dual combination with metformin/

thiazolidinedione- 50 mg or 100 mg daily.

• Dual combination with a sulfonylurea- 50 mg once

daily in the morning.

• Combination with insulin- 50 mg or 100 mg daily.

• Maximum dose- 100 mg (in two doses).

Patients with chronic kidney disease

Mild Moderate Severe ESRD

eGFR 60-89

mL/min/1.73m2

eGFR 30-59

mL/min/1.73m2

eGFR 15-29

mL/min/1.73m2

eGFR <15

mL/min/1.73m2

No dosage

adjustment

required

50 mg once daily

Precautions

• Limited experience in patients with End Stage

Renal Disease (ESRD) on haemodialysis.

• Not recommended in patients with hepatic

impairment, including patients with a pre-

treatment ALT or AST > 2.5 times the upper limit

of normal.

• LFTs should be monitored during Vildagliptin

treatment at three month intervals during the

first year and periodically thereafter.

• If an increase in AST or ALT of 3 times upper

limit of normal or greater persist, withdrawal of

therapy with Vildagliptin is recommended.

• It contains lactose. Patients with rare hereditary

problems of galactose intolerance, lactase

deficiency or glucose-galactose

malabsorption should not take this medicine.

Adverse reactions

• Dizziness

• Headache

• Constipation

• Peripheral oedema

Saxagliptin

• Dosage and administration

▫ 2.5 to 5 mg once daily regardless of meals

▫ GFR<50 ml/min- 2.5 mg once daily

▫ Concomitant use of Cytochrome P-450 3A

inhibitors (eg: Ketoconazole)- 2.5 mg once daily.

▫ Maximum dose- 5mg in one dose.

• Tablets should not be split or cut.

Precautions

• Acute pancreatitis

• Hypoglycemia

• Hypersensitivity (Urticaria/Facial edema)

Adverse reactions

• Upper RTI

• UTI

• Headache

• Peripheral edema

Linagliptin

• Dosage and administration-

▫ 5 mg once daily.

• No dosage adjustment needed for renal or

hepatic impairment.

• Strong inducer of Cytochrome P-450 3A (e.g-

Rifampin) decrease exposure to linagliptin. For

patients requiring use of such drugs, an

alternative to linagliptin is strongly

recommended.

Precautions

• Acute pancreatitis.

• Hypoglycemia.

• Serious hypersensitivity reactions including

anaphylaxis, angioedema, and exfoliative skin

conditions.

Adverse reactions

• Nasopharyngitis

• Diarrhoea

• Cough

Alogliptin

• Dosage and administration-

▫ 25 mg once daily.

Degree of Renal

Impairment

Creatinine

Clearance

(mL/min)

Recommended

Dosing

Moderate ≥30 to <60 12.5 mg once daily

Severe/ESRD <30 6.25 mg once daily

Precautions

• Acute pancreatitis.

• Hypersensitivity.

• Hepatic failure.

• Hypoglycemia.

Adverse reactions

• Nasopharyngitis

• Headache

• Upper RTI

Drug Duration of

action (Hours)

Preparation Timing with

meal

Maximum

Dose

Sitagliptine 18-24 25, 50, 100 mg ---- 100 mg ( in 1

dose)

Vildagliptine 12-24 50 mg ---- 50 mg (in 2

doses)

Saxagliptine 24 5 mg ---- 5 mg ( in 1

dose)

Linagliptine 24 5 mg ---- 5 mg ( in 1

dose)

GLP-1 agonists

Exenatide• A chemical in the lizard’s

saliva called exendin-4 was

shown to act in a similar

way to the human hormone

glucagon-like-peptide-1

(GLP-1)

Dosage and administration

• The concurrent use with insulin has not been studied and cannot be recommended .

• Inject subcutaneously within 60 minutes prior to morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart).

• Initiate at 5 mcg per dose twice daily; increase to 10 mcg twice daily after 1 month based on clinical response

• It should not be used in patients with severe

renal impairment (creatinine clearance < 30

mL/min) or ESRD.

• Should be used with caution in patients with

renal transplantation.

• Not recommended in patients with severe

gastrointestinal disease including gastroparesis.

Precautions • Pancreatitis.

• Hypoglycemia.

• Renal impairment.

• Severe GI disease.

• Hypersensitivity.

• Co-administration with Warfarin may cause increased INR and bleeding.

• For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before injection.

Adverse reactions • Nausea, which usually decreases over time.

• Vomiting.

• Hypoglycemia.

• Diarrhoea.

• Dizziness.

• Headache.

• Dyspepsia.

Liraglutide

• Human GLP-1

analogue

• Slow absorption from subcutis• Resistant to DPP-4• Long plasma half-life (T½=13 h)

C-16 fatty acid(palmitoyl)

His Ala Thr Thr SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Glu

Arg

7 9

34

Liraglutide

Dosage and administration• Administer once daily at any time of day,

independently of meals.

• Initiate at 0.6 mg per day for one week. This dose is intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control.

• After one week, increase the dose to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg (maximum dose) .

Contraindications

• Do not use in patients with a personal or family

history of medullary thyroid carcinoma or in

patients with Multiple Endocrine Neoplasia

syndrome type 2.

Precautions

• Pancreatitis.

• Serious hypoglycemia.

• Thyroid C-cell tumors in animals.

Adverse reactions

• Headache.

• Nausea.

• Diarrhoea.

• Anti-liraglutide antibody formation.

• Vomiting.

• Upper Respiratory Tract Infection.

• Urinary Tract Infection.

• Dizziness.

• Sinusitis.

• Nasopharyngitis.

Similarities of incretin-based therapies

Differences of incretin-based therapies

Clinical benefits from using incretin-

based glucose lowering medications

• Effective lowering of fasting and postprandial glucose.

• No stimulation of insulin secretion at low glucose (avoidance of hypoglycemia).

• No risk of body weight gain.

• Reduction systolic blood pressure.

• Durability better than with sulfonylureas.

• Prevention of microvascular diabetes complications based on glucose-lowering effects.

• Potential to prevent cardiovascular events and mortality.

Adverse outcomes from using

incretin- based glucose lowering

medications• Nausea, vomiting, diarrhea, and other

“gastrointestinal” adverse events.

• Pancreatitis associated with the use of GLP-1 receptor agonists and DPP-4 inhibitors.

• Pancreatic cancer hypothesized to be a long-term consequence of using incretin-based glucose-lowering drugs

• C-cell proliferation (hyperplasia, adenomas, medullary thyroid cancer) induced by GLP-1 receptor agonists in rodents