vildagliptin

VV ildagliptini ldagliptinVILDAGLIPTIN:VILDAGLIPTIN:

DPPDPP -- IV INHIBITORIV INHIBITOR

By sirinoot Jantharangkul4827038

VVildagliptinildagliptin

Generic name: VildagliptinBrand name: GalvusTreatment for: type 2 diabetesselective inhibitor of dipeptidyl- peptidase IV (DPP-IV)

T2DM (Type 2 diabetes mellitus)

The incidence is increasing

There are approximately 110 mill ion people with diabetes at present but this number wil l reach over and the 220 mill ion by the year 2010

Introduction

T2DM (Type 2 diabetes mellitus) A disease of progressive β-cell

dysfunction in presence of insulin resistance

Leading to gradual loss of glycemic control

The pathological loss of β-cell function may be the result of a number of factors including β-cell secretory defects glucotoxicity due to hyperglycemia l ipotoxicity due to disl ipidemiapossibly abnormalit ies in secretion or

response to incretin hormones

Introduction

ปจัจ ุบนัพบว ่า คนไข้ T2DM ทุกรายจะม ีการตอบสนองต่อ

ผลของฮอร ์โมนอินคร ิต ิน ลดน้อยลง จึงเปน็หล ักการส ำาคญัทีน่ ำามาใช้เปน็

แนวทางในการพัฒนายา กลุ่มใหม่ท ี่ใช ้ในการร ักษาผูป้ ่วยเบา

หวานชนิดที่ 2 ในปจัจ ุบนั

Introduction

T2DM (Type 2 diabetes mellitus)

Incretin Hormones Introduction

Incretin are hormones released from the gastrointestinal tract

Response to nutrient ingestion that potentiate glucose-stimulated insulin secretion from islet beta cells

“ในคนปกติพบว่า อ ินคร ิต ินฮอร ์โมนมผีลมากถงึร ้อยละ 50-70 ท ีจ่ะกระต ุ้นต ับอ ่อนให้

สร ้างฮอร ์โมนอินซลู ิน”

The 2 predominant incretins GIP (glucose-dependent insulinotropic peptide)GLP-1 (glucagon l ike peptide-1)

Incretin Hormones

GIP(Glucose-dependent insulinotropic polypeptide)

42-amino acid polypeptide Secreted from the K-cells after ingestion of carbohydrates fat and amino acids

duodenum proximal jejunum

“ fat being the most potent st imulator of GIP secretion”

GIP acts through a specif ic GIP-receptor in the β-cell plasma membrane The binding of GIP at the receptor on pancreatic β-cell enhances exocytosis of insulin contain in granules

GLP-1 is a 30 amino acid peptide

Stored in the L-cells - i leum - colonReleased in response to meal

ingestion with l ipids and carbohydrates being most potent in stimulating secretion

The mechanism of the insulinotropic action

- specif ic GLP-1 receptor belonging to the

glucagon subfamily of G-protein-coupled

receptors

GLP-1 (glucagon-like peptide-1) Introduction

GLP-1 GIP

Insulin

Glycogen-synthesis Glucose-uptake Lipogenesis

++

++

++

++

++

L-cells K-cells

StomachGastricemptying

BrainSatiety

-

++

Beneficial effects of GLP-1 Stimulation of insulin secretion Suppression of glucagon secretion Stimulation of insulin biosynthesis Slowing of gastric emptying Induction of a sense of satiety and

fullness Reduction in food intake Stimulation of proliferation and

suppression of apoptosis in β-cells

Actions of Glucagon-Like Peptide-1Introduction

DPP-4 (Dipeptidyl peptidase-4)

The enzyme that rapidly inactivates GLP-1

His Ala Glu Gly ThrPheThr SerAsp

Lys Ala Ala Gln Gly Glu Leu Tyr Ser

Ile Ala Trp Leu Val Lys Gly Arg Gly

Val

Ser

Glu

Phe

Glu Gly ThrPheThr SerAsp

Lys Ala Ala Gln Gly Glu Leu Tyr Ser

Ile Ala Trp Leu Val Lys Gly Arg Gly

Val

Ser

Glu

Phe

DPPIV

GLP-1 (9-37)GLP-1 (9-37)InactiveInactive

GLP-1 (7-37)GLP-1 (7-37)ActiveActive

Two new classes of agents The incretin mimetics

ExenatideLiraglutide DAC:GLP-1

The DPP-IV inhibitorsVildagliptin(LAF237)Sitagliptin (MK 0431)

Incretin-based therapies

Exenatide

Vildagliptin

•the f irst in a new class of oral antidiabetic agents

•known as dipeptidyl peptidase IV inhibitors

(DPP-IV) inhibitors

"incretin enhancers"

(2S)-([(3-hydroxyadamantan-1-yl )amino]acetyl)-pyrrolidine-2-carbonitri le

Mechanism of action

Absorption/Distributionrapidly and almost completely absorbed (~85% of administered

dose) after oral administrationthe pharmacokinetics are not

affected by foodT max : 1–2hoursplasma protein binding 4-17%

PharmacokineticsPharmacokinetics

Metabolism/Elimination half- l i fe : 1.5–4.5 hr Most of the drug is metabolised with hydrolysis of the cyano moiety dominating (55%) A fraction (22%) is also excreted

unchanged by the kidneys. minimally metabolised by the major cytochrome P450 enzymes

PharmacokineticsPharmacokinetics

neither an inhibitor nor an inducer of P450 enzymes

Drug interactionsDrug interactions

monotherapy and in combination with other antidiabetic treatments has proved to be well tolerated for periods up to 52 weeks

HHypoglycaemiaypoglycaemia is low and similar to that with metformin or rosiglitazone

No apparent weight gainweight gain or edemaedemaGI side effectsGI side effects is comparable to placebo

and is much less than in metformin- treated patients

CCardiac adverse eventsardiac adverse events and HHypertensionypertension with vildagliptin is comparable to placebo and is also less than with metformin

Side EffectsSide Effects

Vildagliptin is taken orally and is l ikely to be administered once daily.

Oral 50 and 100 mg in cl inical tr ial in type 2 DM

No adjustment of dose is necessary in either heptic or renal insufficiency

Dosage and administrationDosage and administration

Summary

Vildagliptin is the first of a new class of drugs for the treatment of Type 2 diabetes.

This group of drugs wil l be known as DPP-IV (dipeptyl peptidase-IV) inhibitors.

Reduces blood glucose concentrations by enhancing the effects of

“ incretins”

Summary

Well tolerated - low rates of adverse effects in clinical tr ials

Not associated with weight gain

Clinical Clinical studies 1studies 1Clinical Clinical

studies 1studies 1

Phase III Trial Design for Study 2309 . Long-term LAF237 Monotherapy Drug naïve patients with T2DM and HbA1c 7.5-11% Objective - HbA1c reduction at 12 months and maintenance

to 2 years

Source: Study 2309 data on fi le17 London Pharmaceutical Pipeline Event 2005 / Ameet Nathwani

52 Week Data with Monotherapy Confirm Earlyand Sustained Reductions in HbA1c

Both LAF237 and Metformin DemonstrateBody Weight Neutrality Unlike SUs1 and TZDs2

LAF237 is Better Tolerated than Metformin

LAF237 Has a Superior GI Tolerability Profileto Metformin


studies 2studies 2

Phase III Trial Design for Study 2329 . LAF237Dose Comparison

Drug naïve patients with T2DM and HbA1c 9-11% Primary objective: HbA1c reduction from baseline . LAF237 50 mg

and 100 mg total daily dose Pioglitazone used as a positive control for study validation

LAF237 Demonstrates Excellent Responder Rates

LAF237 Achieves Excellent, Dose-proportionalReductions in HbA1c


studies 3studies 3

Phase IIb Trial Design for Study 1202- LAF237Dose-ranging Study

Drug naïve patients with T2DM and HbA1c 7.5-11% Primary objective: HbA1c reduction from baseline .

LAF237 20 mg,50 and 100 mg vs. placebo

LAF237 Demonstrates Excellent, DoseproportionalReduction in HbA1c

LAF237 New Phase IIb/III Data Summary

Reduces HbA1c levels in a dose- proportional, cl inically meaningful manner in monotherapy and combination with insulinSustains meaningful HbA1c reductions out to one yearHas neutral body weight effects associated with HbA1c

improvementsIs very well tolerated

Is associated with fewer severe hypoglycemic episodes when added to insulin

Has the ideal profi le as .f irst drug of choice. for combination treatment due to eff icacy and safety profi le, lack of drug-drug interactions and complementary mechanism of action

LAF237 New Phase IIb/III Data Summary

Biguanides

Metformin or Metformin ER (Glucophage)Inhibits hepatic glucose production and

decreases insulin resistanceLowers FBS 40-60 mg/dl and A1c 1-2 %Pros: no hypoglycemia and small weight

lossCons: GI intolerance, contraindicated in

renal insufficiency and acute CHF

Thiazolidinediones

Pioglitazone (Actos) or Rosiglitazone (Avandia)Decrease insulin resistance and improve beta

cell functionLowers FBS 30-60 mg/dl and A1c 0.5-1.9 %Pros: no hypoglycemia and safe in CRICons: weight gain, edema, risk of CHF and cost

Combination Drugs

SU + metformin (Glucovance, Metaglip)SU + TZD (Avandaryl)Metformin + TZD (Avandamet and

Actoplusmet)Lower A1c 2 – 4 %Pros: cost savings, convenience, improved

adherenceCons: limited flexibility

Incretin Mimetics

Exenatide (Byetta)Mechanism of Action:

- increases insulin secretion - decreases glucagon secretion - delays gastric emptying - promotes satiety and weight loss - increases beta cell mass

Lowers FBS 10-20 mg/dl, A1c 1%

Prevalence of T2DM Projected to Double Within 25 Years

Incretin Mimetics

Pros: no hypoglycemia, weight lossCons: GI intolerance, requires injection and

refrigerationNewer agents in development

- liraglutide (acylated GLP-1 analogue) - exenatide-LAR - vildagliptin, sitagliptin (DPP-IV inhibitors; orally active, but weight neutral)

Prandial Regulators

Meglitinides - repaglinide (Prandin) - nateglinide (Starlix)

Stimulate insulin secretion Lower A1c 1-2 % (Prandin) or 0.5-1 % (Starlix) Short half-life; dosed tid with meals Pros: less hypoglycemia than SU, potential CV

benefit Cons: cost, requires frequent dosing

Prandial Regulators

Alpha-glucosidase inhibitors - precose (Acarbose) - miglitol (Glyset)

Delay carbohydrate absorptionLower FBS 20-30 mg/dl, A1c 0.5-1 %Pros: no hypoglycemia, weight neutral,

possible CV benefitCons: GI intolerance, cost, frequent dosing

Approachs to Type 2 Diabetes

Insulins

Basal insulins - glargine (Lantus): peakless, 24 hr - detemir (Levemir): small peak, ≤ 24 hr

Pros: less hypoglycemia, BS variability and weight gain than NPH; usually given once daily

Cons: cost

Insulins

Rapid acting insulins- lispro (Humalog)

- aspart (Novolog) - glulisine (Apidra)

Pros: improved PPG, less hypoglycemia, and improved convenience when compared with regular insulin

Cons: cost

Inhaled Insulin

Exubera (inhaled powdered insulin)Pros: kinetics similar to rapid acting

injectable insulin analogs, does not require injection

Cons: inhaler device, contraindicated in smokers and patients with lung disease, limited ability to titrate dose, and cost

Insulin Mixtures

Humalog 75/25 and 50/50Novalog mix 70/30Pros: improved PPG, less hypoglycemia

and preferred pen delivery compared with Humulin 70/30

Cons: cost

Pramlintide

Pramlintide (Symlin); a synthetic amylin analogue

Mechanism of Action: - inhibits glucagon secretion - slows gastic emptying - promotes satiety and weight loss

Pros: lowers PPG, lowers A1c 0.5 % and promotes weight loss

Cons: GI intolerance, hypoglycemia, another injection, and cost

DPP-IV Inhibitors (liptins)

Sites of Action for Oral Therapies for Type 2 DM

vildagliptin

Health & Medicine