ANTIDIABETICAGENTS

Jiří Slíva

DIABETES MELLITUS

• Multifactorial disease with genetic component

• Main symptoms: hyperglycemia, metabolic disturbances

• Relative or total absence of insulin → increase of the glucose blood level

• Borderline DM: concentration of glucose plasma level 7.0 mmol/L – fasting and 11.1 mmol/L 2 hours after the meal

TYPE l diabetes (IDDM, insulin-dependent diabetes mellitus)

• Formerly juvenile diabetes

• LADA (latent autoimmune diabetes in adults)

• Total absence of insulin

• Langerhans islets B-cells lesion (usually caused by autoimmune disease) → infiltration of islets with T-lymphocytes

• Antibodies against islets tissue and insulin

TYPE ll diabetes (NIDDM, non-insulin dependent diabetes mellitus)

• Formerly senile diabetes (onset in adulthood)

• Relative absence of insulin

• Levels of insulin could be normal or above or below normal

• Insulin-sensitive tissues show a lack of insulin-sensitivity or a reduction of insulin receptors is supposed

• NIDDM patients are often obese

ANTIDIABETIC AGENTS

DM l. type treatment• Insulin

DM ll. type treatment (PAD)• Sulphonylureas• Biguanides• α-glucosidase inhibitors• Glitazones (thiazolidinediones)• Glinides etc.

INSULIN

• Human insulin – low molecular protein– strong electronegative (binding to positively charged

proteins in circulation and to membrane insulin receptors)

– two peptide chains A (21 AAs) a B (30 AAs), linked by disulphide bridges

Structure of human insulin

INSULIN

• Proteohormone

- glucose utilization

- metabolism of lipids and proteins

(storage of these basal sources, „anabolic“ hormone)

Lack of insulin

(either absolute of relative)

►DIABETES MELLITUS

INSULIN SECRETION

Daily production: 20 – 40 IU

• Basal secretion (cca 50 %)- independent on food intake- blocks glucose production in liver- responsible for fasting euglycaemia

• Stimulated secretion (cca 50%) - stimulated by food intake- regulates postprandial glycaemia

INSULIN TREAMENT INDICATIONS• DM type 1• Some DM type 2 patients or patients with secondary diabetes

• Insulin treatment in DM type 2 patients• PAD treatment failure• Allergy to PAD• Diabetes in pregnancy• Severe renal or liver insufficiency• Clinical situations with contemporary decompensated

diabetes (operation, infection, etc.)

INSULIN SYNTHESIS

• preproinsulin → proinsulin → insulin a C-peptide (shows the endogenous insulin secretion)

• Insulin release from pancreatic B-cells each 15 -30 min

HEALTHY

DIABETIC PATIENT

INSULIN RELEASE FROM B-CELLS

Controlled by glucose concentration

a) influx of glucose to the B-cell by GLUT-2 transporter b) metabolism of glucose by glukokinase c) increase of ATP concentration in the cell d) closure of ATP-sensitive potassium channels e) depolarization and opening of voltage-sensitive

Ca2+ channels f) degranulation of B-cells and insulin release to the

extra cellular space

INSULIN RECEPTORS

• glycoproteins (muscle, adipose tissue)

• two heterodimers linked by disulphide bridges, each consists of α- and β- subunit

• α-subunit – extra cellular, binding place for insulin

• β-subunit – transmembrane protein with tyrosine kinase activity

Figure : Insulin-receptor complexes on the cell surface cause chemical responses to occur within the cell. This figure was reproduced pending permission from the authors of Life, 6th Ed (Purves et al, 2001).

INSULIN EFFECTS

• The main hormone of metabolic processes in liver, muscle and adipose tissue

• stimulates anabolic and inhibits catabolic processes

• Facilitates gathering of glucose, aminoacids and lipids from food

• Acute effect of insulin ►hypoglycemia

ACUTE CONSEQUENCES OF INSULIN SHORTAGE

• Lack of insulin in glucose metabolism → hyperglycemia

• Osmotic diuresis → polyuria

• Renal loss of water, Na+ and K+ → dehydration, thirst

• Dehydration → hypovolemia

• Release of fatty acids →hyperacidlipidemia

INSULIN THERAPY

• The daily dose as low as possible!

(up to 40 IU / day)

• Shorter-acting insulin

→ more doses daily

→ better compensation of DM

→ using lower daily dose

INSULIN THERAPY

• „Conventional“ therapy

- insulin in one or two daily doses(good compensation just in type 2 DM patients)

• „Intensified“ therapy

- covers basal and prandial need of insulin(more doses, better compensation, lower daily dose)

ANIMAL INSULIN SOURCES

• bovine and porcine pancreas

→ complicated purification

• Bovine insulin is different from human insulin in three amino acids, porcine in one amino acid

• human insulin

ADVANTAGE: less allergic reactions

CLASSIFICATION OFINSULIN PREPARATIONS

• According to sources and purity

• According to duration of action

CLASSIFICATION OFINSULIN PREPARATIONS

• Sources and puritySources and purity– Animal– Human– Insulin analogues

• Duration of actionDuration of action– Short-acting– Intermediate-acting– Long-acting– Combined (mixtures)

ANIMAL INSULINS

• Bovine

• Porcine

• Mixtures

According to level of purity

• Chromatography purified (PUR)

• Highly purified – monocomponent (MC)(significantly less contaminated)

HUMANE INSULINS (HM)

• emp insulin – enzyme techniques to modify porcine insulin

• crb insulin – chain recombinant DNA in bacteria

INSULIN ANALOGUES

• short-acting (glulisine)

• intermediate-acting (lispro)– chain recombinant DNA in bacteria technique– the penultimate lysine and proline residues on the C-

terminal end of the B-chain are reversed

• long-acting (glargine, detemir)

DURATION OF ACTION

• Short-acting - onset 30 minutes, peak 2-4 hoursSoluble simple insulinLispro

• Intermediate- and long- acting - duration of action between 16 and 35 hoursSemilente (suspension, amorphous insulin zinc)

Lente (suspension, mixture,amorphous insulin zinc, insulin zinc crystals)

Isophan insulin (NPH)(complex of protamine and insulin)

Ultralente (suspension, poorly soluble insulin zinc crystals)

• Combined - fixed mixtures (biphasic,..)

Time profiles

Pharmacokinetics of insulin

• The speed of absorption depends on pharmaceutical properties, dosage, and tissue perfusion

• Practically no plasma protein binding

Degradation of insulin:• kidneys (35‒40 %), liver (60 %), the opposite in

exogenous insulin• biologic half-life: 7‒10 minutes• hydrolysis of S-S bridges between A and B chains by

insulinase• further degradation by proteolysis

Adverse reactions: acute

• hypoglycemic reaction – in insulin over dosage, inadequate caloric intake (less food), higher physical activity → sympathetic reaction (sweating, tremor, tachycardia, weakness) and → parasympathetic reaction (hunger, nausea, „clouded“ vision)

• Hypoglycemic coma – i.v. glucose (20‒50 ml 40% Glu) or glucagon

(i.m., s.c.), than glucose or sweet drinks p.o.

Adverse reactions: long-term

• Long term therapy with repeated episodes of hypoglycemia (namely in older patients) => CNS disturbances (fuzziness, incoordinated speech, bizzare behavior)

Insulin application

Application forms

Insulin syrretes

• Special plastic syrretes, volume 1 ml with sealed needle

• 1 scale segment = 1 IU of insulin

• Single use

• Most common application form (adults)

• CheapNote: One international unit of insulin (1 IU) is defined as the "biological equivalent" of 34.7 μg of pure crystalline insulin. This corresponds to the old USP insulin unit, where one unit (U) of insulin was set equal to the amount required to reduce the concentration of blood glucose in a fasting rabbit to 45 mg/dl (2.5 mmol/L).

Application forms

Insulin pens

• Injectors like pen

• Extensible needle

• Perfect for intensified insulin therapy

Structure of insulin pen

Application forms Insulin pumps

• subcutaneous continual infusion

• highly reliable, digital, miniature

• advantage: exchange each 48 hours, comfortable for the patient

• disadvantage: expensive, repeated measurement of glycemia during the day, higher risk of cutaneous infection (permanent needle)

Inhalable insulin

• currently not available

• previously approved in U.S (Exubera)

• effective, but no better than injected short-acting insulin

• it is unlikely to be cost-effective

• in 2011 announced that when applied deep into the nostrils may delay the onset of Alzheimer's disease

Note: under development ‒ buccal spray, insulin pills, insulin patch, …

ORAL ANTIDIABETIC

DRUGS

Oral Antidiabetic Drugs

Classification of oral antidiabetics:Classification of oral antidiabetics:• Sulphonylureas• Biguanides• Intestinal glucosidase inhibitors• Glitazones (thiazolidinediones)• Glinides• Gliptins (syn. dipeptidyl-peptidase 4 (DPP-4) • SGLT inhibitors

Other antidiabetics:Other antidiabetics:Incretinoenhancers

Oral Antidiabetic Drugs

• insulin „sensitizers“– biguanides – glitazones (thiazolidinediones)

• insulin „secretagogues“– sulphonylureas – fast (short) insulin secretagogues (Glinides)– incretins and DPP-4 Inhibitors

• Intestinal glucosidase inhibitors• SGLT inhibitors

Biguanides

• Mechanism of action:– peripheral insulin uptake enhancement (skeletal

muscle,...)

• Main drugs: – metformin

• Adverse effects: – lactate acidosis

Glitazones (Thiazolidinediones)

• Mechanism of action: – peripheral insulin receptors sensitization– targeting peroxisome proliferator-activated receptor (PPAR-

gamma)– improving insulin resistance

• Main drugs: – Pioglitazone (Actos)– [Rosiglitazone (Avandia) – withdrawn in 2010, because of

problems with cardiovascular safety)]

• Adverse effects: – hepatotoxicity– congestive heart failure…

Sulphonylureas

• Mechanism of action : insulin secretion stimulation

• Main drugs: Tolbutamide, Glibenclamide, Glipizide, Gliclazide

• Adverse effects : hypoglycemia

Fast (short) insulin secretagogues: glinides

• Mechanism of action: – insulin secretion stimulation (glycaemia dependent)

• Main drugs: – repaglinide, nateglinide

• Adverse effects: – hypoglycemia, GIT disturbances

x

Sulphonylureas vs. glinides

Sulphonylureas Glinides1) moderate to long-lasting eff.

2) 1x or 2x daily

3) decreased FBG

4) low eff. on the early secretion of insulin

5) low influence of postprandial glycaemic oscilation

6) clinically significant risk of hypoglycaemia (mostly at night)

7) weight gain 2–4 kg

8) average decrease of HbA1c: 1.5 %

9) lower price

1) short action

2) administration with each meal

3) postprandial decrease of glycaemia

4) improved postprandial secretion of insulin

5) signif. influence of PP glycaemic oscilation

6) low risk of hypoglycaemia

7) lower weight gain

8) average decrease of HbA1c is comparable in repaglinide; nateglinide: 0.8 %

9) higher price

Intestinal (Alpha) Glucosidase Inhibitors

• Mechanism of action: – decrease of intestinal carbohydrate absorption

• Main drugs: – acarbose– miglitol

• Adverse effects: – diarrhoe

Physiology of incretins

Note: GLP-1 …Glucagon-like peptide 1; GIP …glucose-dependent insulinotropic polypeptide

Baggio LL, 2007

Physiology of GLP-1

Drucker D, 2006Note: Glucagon-like peptide 1 (GLP-1)

Physiology of GIP

Baggio LL, 2007Note: GIP …glucose-dependent insulinotropic polypeptide

Structure of GLP-1 and incretinomimetics

Drucker D, 2006

Gliptins: mechanism of action

Lauster CD, 2007

- inhibitors of dipeptidyl

peptidase-4 (DPP-4)

= incretin enhancersincretin enhancers =>

increased level of GLP-1

& GIP

GIP …glucose-dependent insulinotropic polypeptide

• sitagliptin, vildagliptin, saxagliptin

Gliptins + metformin

Fonseca V, 2007

HbA: Hemaglobin A; ITT: Intent to treat; LAF: Vildagliptin; MET: Metformin; PBO: Placebo

Characteristics and effects of GLP-1 receptor agonists and DPP-4 inhibitors

Ahrén B, 2011

Glycosuric agents

Marsenic O, 2009

Glycosuric agents

• dapagliflozin– SGLT-2 inhibitor

Marsenic O, 2009

Petr Potměšil

• Extension of presentation about antidiabetics

Possible risk of pancreatic damage after use of drugs influencing incretins

Increased incidence of pancreatitis (?)actually re-assessment of safety in course by EMA,

no change in recommendations for therapy available at the moment (published in Mar-2013, details: www.ema.europa.eu)

• DPP-4 inhibitors (inhibitors of dipeptidylpeptidase IV)

SitagliptinVildagliptinSaxagliptin

• Analogues of GLP-1 (glucagone like peptide)

• Liraglutid

• Agonists of receptor for GLP-1

• Exenatid

Diabetes – comparison of metabolic effects of insulin and glucagone

A/ Insulin

• 1) ↑ oxidation of glucose and ↓ gluconeogenesis

• 2) ↑ synthesis of glycogen and lipids

• 3) anabolic effect

B/ Glucagone

• 1) ↑ glycogenolysis

• 2) hyperglycaemia

Comparison of pharmacokinetic parameters of sulphonylureas and biguanides

A/ Sulphonylureas• ↑ binding to plasm.

proteins• ↑ biotransformation,

thus contraindicated in patients with severe impairment of hepatic/renal function

B/ Biguanides• do not bind to plasm.

proteins• no extensive

biotransformation, elimination mainly by renal excretion, thus contraindicated in patients with severe impairment of renal functions

Some treatment options fordiabetic neuropathic pain

• Tricyclic antidepressants: low tolerability (antimuscarinic eff.)• SSRI - limited efficacy: sometimes not recommended for pain• SNRI antidepressants (AE: disturbed sleep at start)

1/ venlafaxine (Effectin): ↑ dose - possible hypertension 2/ duloxetine (Cymbalta): also approved for urinary stress

incontinence and GAD (general. anxiety disorder)• Antiepileptic drugs (AE: sedation, weight gain)

1/ gabapentin (Neurontin)2/ pregabalin (Lyrica), also for GAD, improves sleep

3/ carbamazepin – many interactions with other drugs