DM Pharmacotherapy

Edy Junaidi

Diabetes Mellitus

⇨ A group of chronic metabolic disorders characterized by hyperglycemia that may result in long-term microvascular, macrovascular, and neuropathic complications

⇨ DM is the leading cause of ⇨ New cases of blindness among adults⇨ End-stage renal disease⇨ Non-traumatic lower limb amputations

⇨ Contribution on increasing cardiovascular risk

DM⇨ Type 1 (previously known as IDDM, juvenile-onset

DM)⇨ Usually diagnosed in children and adults younger than 30

years of age although the disease can present at any age⇨ Characterized by absolute insulin deficiency⇨ LADA (latent autoimmune diabetes in adult) – slow onset

type 1 or Type 1.5 DM → occur at older age than the usual age of onset; Often mistakenly diagnosed as Type 2

⇨ Type 2 (previously known as NIDDM, adult-onset DM)⇨ 90 – 95% of all diagnosed cases⇨ Usually preceded by pre-diabetes⇨ Insulin resistance or relative insulin deficiency

⇨ Other specific types (WHO/NCD/NCS/99.2)

The easiest way of differentiating Type 1 and Type 2 is by measuring C-peptide level : < 1 ng/ml (type 1); Type 2 > 1 ng/ml

Disorder of glycaemia: Etiological type & clinical stages

Clinical presentation of DM

Criteria for Diagnosis of DM

Cook et al., 2008, pp.684 - 707

Uncontrolled DMUncontrolled DM

Pharmacotherapy⇨ Insulin⇨ OAD :

⇨ Sulfonylurea secretagogues⇨ 1st generation : acetohexamide, tolazamide, tolbutamide,

chlorpropamide⇨ 2nd generation : glipizide, glimepiride, glyburide

⇨ Non-sulfonylurea secretagogous (nateglinide, repaglinide)⇨ Biguanide (Metformin)⇨ α-glucosidase inhibitor (acarbose, miglitol)⇨ PPARγ agonist → Thiazolidinediones – insulin sensitizer

(pioglitazone, rosiglitazone)⇨ Dipeptydil peptidase-4 inhibitors (DPP-IV inhibitors:

sitegliptin)

Regulation of blood glucoseRegulation of blood glucose

Insulin⇨ Key tissue target of insulin in regulating of

glucose : Liver, muscle and fat

Regulation of insulin secretion⇨ Involve interplay of : GI hormones, pancreatic

hormones, & autonomic neurotransmitter– In general, any conditions that activate sympathetic nervous system (hypoxia, hypoglycemia, exercise, severe burns, surgery, etc) suppresses insulin release by stimulation of α-adrenergic receptor.

–Oral glucose provoke insulin release better than if its administered intravenously; Oral route stimulate GI hormones & vagal activity, the most potent of which are Glucagon-dependent insulinotropic peptide (GIP) & glucagon-like peptide 1 (GLP-1)

Voltage-gated

ATP-dependent

Insulin signaling pathway

Physiological Effects of Insulin• Increases the number of glucose transporters in the

membrane; it may also increase the rate at each transporter.

• Alters the concentration of fructose 2,6-bisphosphate, which in turn dramatically alters the activity of phosphofructokinase and fructose 1,6-bisphosphatase.

• Increases the activity of pyruvate kinase but inhibits the activity and the synthesis of phosphoenolpyruvate carboxykinase.

• Iincreases the activity of pyruvate dehydrogenase, probably through the insulin mediator

• Promotes lipogenesis and forms fats for storage from glucose through acetyl CoA.

• Promotes the synthesis of glycogen by increasing the activity of glycogen synthase (independent form).

• Inhibits the breakdown of glycogen by inhibiting glycogen phosphorylase.

Goodmann & Gillman, 2008

Classification of Insulin• Short- and Rapid-acting Insulin

– Short acting insulin before or after meal– All rapid acting insulin may be administered

postprandially to provide smoother glycemic control and to prevent hypoglycemia

• Intermediate acting insulin– Usually given once a day before breakfast or twice

a day– In T2DM patients, intermediate acting insulin given

at bedtime may normalize fasting blood glucose• Long acting insulin

– Provide low basal concentration of insulin throughout the day

Indication

• Management of type 1 DM • Management of type 2 DM which is not

controlled by diet &/ OAD alone, • Post pancreatectomy diabetes• Gestational diabetes• Diabetic ketoacidosis• Non ketotic coma • Perioperative management of patient with

type 1 & type 2 DM

Adverse Effects• Hypoglycemia• Insulin allergy & resistance• Lipoatrophy & lipohypertrophy

– Atrophy probably is immune response to insulin

– Hypertrophy is considered as lipogenic action of high local insulin at the site of injection

• Both problems are rare with more purified preprarations

• Insulin edema

Sulfonylurea⇨ Insulin secretion enhancer

SUR = specific sulfonylurea receptor

⇨ Classification of sulfonylurea based on :⇨ Difference in relative potency⇨ Relative potential side effects⇨ Different protein binding properties

⇨ All sulfonylurea are equally effective at equipotent doses

⇨ All sulfonylurea are metabolized in liver (CYP450 2C9); metabolites status : active (less potent, equally potent), inactive

⇨ Half-life directly relate to the risk of hypoglycemia → cautious use in patient with hepatic or renal impairment

⇨ Adverse effects :⇨ Hypoglycemia⇨ Hyponatremia⇨ Weight gain⇨ Skin rash⇨ Hemolytic anemia⇨ GI upset⇨ Cholestasis

⇨ Drug interactions :⇨ Close monitoring concomitant use of CYP450 2C9 inducer

/inhibitor with sulfonylurea

Glinides⇨ Short-acting insulin secretagoguesShort-acting insulin secretagogues (repaglinide,

nateglinide)Mechanism of action :

⇨ Repaglinide closes ATP-dependent potassium channels in the β-cell membrane by binding at characterizable sites → potassium channel blockade depolarizes the β-cell, which leads to an opening of calcium channels → increased calcium influx induces insulin secretion.

⇨ The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle

Kinetics:⇨ Rapidly absorbed, short half-life (1 – 1.5 hours)⇨ Nateglinide predominantly metabolized by CYP450 2C9

(70%) and CYP3A4 (30%), renal elimination; repaglinide predominantly metabolized by CYP3A4, excreted in bile

Efficacy⇨ Both (monotherapy) significantly reduce postprandial

glucose and HbA1c level

⇨ Lower efficacy of glinides vs sulfonylureas should be considered when patients are >1% above their HbA

1c goal

Adverse effects⇨ Hypoglycemia (less than sulfonylurea)

⇨ Rates of hypoglycemia : 3% with nateglinide, 15% repaglinide vs glyburide (15%) & glipizide (19%)

⇨ Weight gain : 2 – 3 kg with repaglinide, < 1 kg with nateglinide

Drug interaction⇨ No significant drug interaction have been reported

Biguanide

⇨ Metformin : the only biguanide available in use⇨ (Phenformin & Buformin withdrawn from market due to toxic

effects)⇨ Enhance insulin sensitivity in liver and

peripheral (muscle) tissues⇨ No direct effect on β-cells⇨ Mechanisms:

⇨ AMP-activated protein kinase activity, tyrosine kinase activity enhancement, glucose transporter 4 are all contributes on the activity of metformin

Kinetics :⇨ 50 – 60 % oral bioavailability⇨ Low lipid solubility; Vd approximate body water⇨ Metformin is not metabolized & does not bind to plasma

protein⇨ Eliminated by renal tubular secretion & glomerular

filtration⇨ Average half-life 6 hours

Efficacy⇨ Consistently reduce HbA1c level by 1.5 – 2 %⇨ Reduce fasting plasma glucose 60 – 80 mg/dl⇨ Retain its glucose-reducing ability at extremely high

glucose level (>300 mg/dl)⇨ Reduce plasma triglycerides & LDL-C by 8 - 15%

Adverse effects:⇨ GI side effects :

⇨ Abdominal discomfort, stomach upset, &/ diarrhea in approximately 30% of patients

⇨ Anorexia & stomach fullness → contribute on weight loss effect of metformin

⇨ GI side effect tend to be transiet, lessening within several weeks⇨ Lactic acidosis (rare)⇨ Metformin is contraindicated in renal insufficiencycontraindicated in renal insufficiency (renal

elimination)

Drug interaction:⇨ Cationic drugs may compete on renal tubular secretion

:cimetidine, procainamide, digoxin, quinidine, trimethoprim, vancomicin

Peroxisome Proliferator Activator Receptor - γ agonists (PPARγ)

Glitazones⇨ PPARγ primarily located on fat cells & vascular

cells⇨ Glitazones – PPARγ receptor interaction →

maturation of preadipocytes (small fat cells are more sensitive to insulin & more able to store FFA) → influx FFA out of plasma, fat, & liver into subcutaneous fat less insulin-resistant storage- tissue

⇨ Muscle intracellular fat products, which contribute to insulin-resistant, also decline

Kinetics:⇨ Well absorbed & highly bound to protein plasma⇨ Half-life: pioglitazone:3 – 7 hours, rosiglitazone 3 – 4

hours⇨ Active metabolites with longer half-life deliver the

majority of activity at steady state⇨ Both have 24 hours duration of antihyperglycemic activity

Efficacy⇨ Reduce HbA1c 1.5%, lower glucose (FPG) level 60 – 70

mg/dl at maximal doses⇨ Glycemic lowering onset is slow, maximal effect may not

observed until 3 – 4 months therapy⇨ The efficacy of both drugs is dependent on sufficient

insulinemia

Adverse effects:⇨ Troglitazone, the first thiazolidinedione, were removed

from market in March 2000 because of idiosyncratic hepatotoxicity resulting in 28 deaths

⇨ No evidence of hepatotoxicity in more than 5.000 patients given pioglitazone & rosiglitazone

⇨ It is recommended to check ALT periodically (every 2 months on the 1st year of therapy)

⇨ Patients withALT level >2.5 times of upper limit of normal should not start either medication

⇨ Patient on medication with ALT level > 3 times of upper limit of normal, medication should be STOP

⇨ Fluid retention – edema, dose related⇨ Reduction of plasma Hb⇨ Weight gain

Drug interaction:⇨ No significant drug interaction have been noted with either

medication

α-glucosidase Inhibitor⇨ Competitively inhibit enzymes (maltase,

isomaltase, sucrase, & glucoamylase) in the small intestine, delaying breakdown of sucrose and complex carbohydrate⇨ They do not cause any malabsorption of these nutrients

Kinetics:⇨ Mechanism of α-glucosidase inhibitor is limited to

luminal site of intestine⇨ Some acarbose are absorbed sistemically & renally

excreted, while majority of miglitol is absorbed & renally excreted unchanged

Efficacy:⇨ Reduce postprandial glucose (40 – 50 mg/dl), fasting

glucose level relatively unchanged⇨ Efficacy on glycemic control is modest (reduction in

HbA1c 0.3 – 1%)

Adverse effects:⇨ Flatulence, bloating, abdominal discomfort, and diarrhea

are very common → greatly limit the use of α-glucosidase inhibitors

⇨ Distal intestinal degradation of undigested carbohydrate by microflora → CO

2 & methane production

⇨ Elevated ALT level in high doses of acarbose

Dipeptidyl peptidase-4 Inhibitor⇨ The newest therapeutic class of oral agents for

Diabetes⇨ Sitagliptin is the only FDA approved

(vildagliptin, saxagliptin are in clinical trial www.clinicaltrial.gov)

⇨ DPP-IV inhibitors slow inactivation of incretin hormones within the gut

⇨ Incretin hormones are release throughout the day and increase level with meal

⇨ Drug activity – glucose dependent

⇨ reduce HbA1c 0.7 – 0.8 % compared to placebo⇨ Renal function monitoring recommended prior to

initiation and during treatment

Adverse effects:⇨ Nasopharyngitis (5.2%)⇨ Upper respiratory infection (6.3%)⇨ Headache (5.1%)

⇨ No current drug interaction data available