Principle of Diabetes Principle of Diabetes managementmanagement

Maha M.Al-Rasheed, MSc Maha M.Al-Rasheed, MSc PharmPharm

Lecturer,Clinical Pharmacy Lecturer,Clinical Pharmacy Dept.Dept.

KSUKSU

I. Prevalence:

Estimated that 6 % of the population in the US has diabetes.

More prevalent among minorities

Incidence is twice as high in patients > 65 years of ages vs. those 45-54 years of age.

Leading causes of blindness in adults aged 20-74

Leading causes of end – stage renal disease

>8 $ > ( % 80 Billion ) of US health care dollars is spent on people with diabetes .

II. Definition: A. Carbohydrate Metabolism :

1. Regulation of carbohydrate and fattyacid metabolism is the function of insulin and counterregulatory hormones .

2. Overall effects of insulin:

- glucose removal , glycogen storage , fatty acid storage , protein synthesis -Inhibition of Ketone body formation in the liver at lower concentration of insulin

than those required to stimulate muscles uptake of glucose

B. counterregulary hormones:

●glucagon ( pancereas ) ; epinephrine , cortisol , and GH

●overall effects : increase in glycogenolysis and inhibit insulin release

●Normal CHO metabolism

Postprandial Metabolism

↑Glucose

Insulin Release ( anabolic)

Turns on

Glucose Glycogen

AA Protein

FFA TG

SHUTS OFF

↓Glucose Fasting Metabolism

Counterregularty hormones release Gluccagon

Epinephrine Cortisol

Growith hormone

GlycogenolysisGluconeogensis

Carbohydrate metabolism and diabetes :

- Blood glucose concentration remain elevated after a meal with the absolute or relative lack of insulin

- Since glucose is inaccessible to cells fasting metabolism is triggered

- Further increase in glucose with glycogenolysis and gluconeogenesis

↓Insulin or insulin resistance↓Insulin or insulin resistance

Hepatic glucose output Hepatic glucose output Catabolism Catabolism Lipolysis Lipolysis

↑Glucose Ployuria Polydisia

PolyphagiaLack of energy

Infections Blurred vision

↑Glucose Ployuria Polydisia

PolyphagiaLack of energy

Infections Blurred vision

↑FFAKetosis

Acidosis

↑FFAKetosis

Acidosis

Weight Loss

Stunted GrowthWeight Loss

Stunted Growth(glycogenolysis Glconeogenesis)

(glycogenolysis Glconeogenesis)

Normal plasma glucose is usually maintained at 60-140 mg/dl.

Minimum concentration of 40-60mg/dl is needed for CNS

Resorptive capacity of the kidneys is ~180 mg/dl.

Muscle and fat also used glucose as an energy source , but these

tissues require insulin for glucose uptake.

III. Signs and Symptoms

- Polyuria - Polydipsia . - Polyphagia - Weight loss - Fatigue - Recurrent urinary tract infections, respiratory infections , and others - Ketoacidosis - Blurred vision

Type1Type1Type2Type2

Other NamesOther NamesInsulin – dependent diabetes Insulin – dependent diabetes

mellitus IDDM, type Imellitus IDDM, type INon- insulin dependent Non- insulin dependent

diabetes metllitus , diabetes metllitus , NIDDM, type IINIDDM, type II

Percent of Percent of Diabetic Diabetic

PopulationPopulation

Age at OnsetAge at Onset

Family HistoryFamily History

WeightWeight

KetoacidosisKetoacidosis

Panacereatic Panacereatic FunctionFunction

PathogenesisPathogenesis

Associated with certain HLA Associated with certain HLA types ; presence of islet types ; presence of islet cell antibodies suggest cell antibodies suggest an autoimmune processan autoimmune process

Defect in insulin secretion ; Defect in insulin secretion ; tissue resistance to tissue resistance to insulin; increase in insulin; increase in hepatic glucose hepatic glucose production production

Clinical Clinical presentationpresentation

IV. Classification of Diabetes :

V. Contributing Factors and Etiologies

A. major risk factor for diabetes mellitus

- Family history ) first degree relative , parents or siblings( - Obesity ) ≥20% Over IBW or BMI ≥ 27 Kg/m2 (

- Age ≥ 45 years old - History of impaired glucose ) IGT( or impaired fasting glucose ) IFG(

- HTN )≥ 140/90 mmHg( - HDL ≤ 35 and /or TG ≥ 250

- History of gestational diabetes or delivery of a baby > 9 Ibs

B. high risk ethnic populations :

African - American , Hispanic – American , pacific islander , Native American

C. Drug – induced diabetes

1 .drugs high in sugar content : amount of glucose in OTC and RX liquids is usually not clinically significant

2 .Drugs that increase hepatic glucose output

a( glucocorticoids b( sympathomimetics

3 .Drugs that decrease insulin secretion

a( phenytoin b( beta blockers / calcium channel blockers

4. Drugs that increase insulin resistance

a( thiazide diuretics b( niacin c( glucocorticoids

5. drugs that are toxic to beta cells.

a( pentamidine

6. drugs that stimulate appetite

phenothiazines,marijunana, androgens

D. Endocrine- related disorders: Cushing’s syndrome , hyperthyroidism , acromegaly .

E. pancreas – related disorders : pancreatitis , trauma / pancreatectomy , cystic fibrosis

f. Infections CMV , rubella

G. other genetic syndromes : Down’s syndroms , turner’s syndrome, Huntington’s chorea,

prophyria

IV. Diagnostic Criteria :

* Normal values:

Fasting blood glucose > 100 mg/dl 2-hour oral glucose tolerance test ) OGTT( > 140 mg/dl

Table 2. Table 2. Criteria for the diagnosis of diabetes mellitusCriteria for the diagnosis of diabetes mellitus

1.1.FBG FBG ≥≥ 126 mg / dl x2 occasion 126 mg / dl x2 occasion 2.2.Random glucose > 200 mg/ dl with symptoms of Random glucose > 200 mg/ dl with symptoms of diabetes x2 occasion diabetes x2 occasion 3.3.2hr. postprandial glucose 2hr. postprandial glucose ≥≥ 200 mg / dl during an 200 mg / dl during an OGTT* x 2 occasions OGTT* x 2 occasions *OGTT with a 75gm glucose load *OGTT with a 75gm glucose load

Diabetes care 2004; 27 suppl 4, 2004

Table 3. Criteria including the intermediate PatientTable 3. Criteria including the intermediate PatientFasting Glucose Fasting Glucose

mg/dlmg/dl2-hr OGTT 2-hr OGTT

mg/dlmg/dlRandom Glucose Random Glucose

mg/dlmg/dl

Normal Normal < 100< 100<140<140<200<200

Impaired Impaired Fasting Glucose Fasting Glucose ( IFG)( IFG)

> 100 and < 126> 100 and < 126< 200< 200

Impaired Impaired Glucose Glucose Tolerance Tolerance ( IGT)( IGT)

≥≥ 140 and < 200140 and < 200<200<200

Diabetes ( non- Diabetes ( non- pregnant pregnant

≥≥ 126126≥≥ 200200≥≥ 200200

Diabetes Care 2004 ; 27 suppl 3, 2004

ADA criteria for screening for diabetes in asymptomatic , undiagnosed individual

VII. long – Term complications of Diabetes :

A. microvascular disease 1. Ocular complications 2. Nephorpathy 3. Neuropathy

B. marcovascular disease : 1. coronary heart disease -leading cause of death in the type 2 population 2. stroke 3. peripheral vascular disease -diabetes is the leading cause of nontraumatic amputations C. Periodontal disease

VIII. monitoring parameter and test to Guide management

A. Signs and symptoms B. Blood glucose test ) Home blood glucose monitoring HBGM(

- Fasting ) ADA target is 80-120 mg/dl( - Random or postprandial

- Bedtime glucose ) ADA target is 100-140 mg/dl (

C. Glycosylated hemoglobine)HgbA1c(- Definition :non – enzymatic irreversible glycosylation of hemoglibine A

circulating in blood ; amount formed is related to degree of hyperglycemia

- Reported as percent of hemoglobin - Reflects average blood glucose concentration over the past 8-12 week

Hg AHg A1c1c5%5%6%6%7%7%8%8%9%9%10%10%11%11%12%12%

Av. Av. Blood Blood

GlucoseGlucose9090120120150150180180210210240240270270300300

*A 1% change in the glycosylated hemoglobin can represent a 25-35 mg/dl change in the mean blood glucose

- Advantages

- Disadvantages

d. Urine Tests

E. Others - fasting lipid profile - Blood pressure - Electrolytes

IX. principles of management

A. Goals of therapy

1 .Keep patient asymptomatic 2 .prevent long term complications

3 .Maintain patient near euglycemia 4 .Achieve and maintain an appropriate body weight

5 .maintain normal growth and development in children 6 .Enhance patient and self – reliance in management of the disease

7 .Eliminate or minimize all cardiovascular risk factors

Diet

Exercisedrugs

B. Components of therapy

C. General Approach

1. Educate the patient and family about disease and treatment 2. set realistic goals 3. Formulate a plan for achieving glycemic control 4. obtain agreement with the patient regarding goals and treatment and provide supportive follow up

D. Non- pharmacologic therapy 1. Diet : ADA diet - Moderate caloric restriction - Moderate weight loss - Protein : 10 – 20% of daily caloric intake - > 10 % saturated fats and > 10 % polyunsaturated fats - > 300 mg cholesterol - 20-35 gm fiber 2. Exercise

3. general health maintenance - Weight loss , if indicated - Smoking cessation - Manage cardiovascular risk factors ) Take aspirin (

E. patient education )continuous, disease state, drug therapy(

F. Glucometer instruction G. prevention and treatment of complications 1. Foot care 2. Annual eye exam 3. nephropathy 4. Cardiovascular risk factors

X. The Role of the pharmacist in Diabetes management

A. Pivotal role in the overall management of the diabetic patient B. Obtain patient history and pertinent information

- Record and review all medication including OTCs herbal and vitamins - Monitor patient’s adherence to their therapy . - Counsel on disease state, HBGM, injections, oral medications etc .

C. Assess outcomes D. collaborate with other healthcare professionals

- Work with patient’s primary care provider-May help make recommendations

-Know when to refer patient to another provider E. Documentation is key

Principle of Diabetes managementPart II : treatment

I. Insulin

A. immunogenecity

impurities rare since FDA set requirement of > 10ppm proinsulin

Species source is now the primary immunogenic component

Beef > Pork > human

B. Technology

Biosynthesis : recombinant DNA origin

-Genetic Code for human proinsulin is inserted into the plasmid of E. Coil bacteria or yeast when produce human proinsulin

Connecting peptide is then enzymatically cleaved from proinsulin

After purification , the end products is identical to human insulin

C. Physical and chemical properties

lispro and regular insulin are solution that can be given IV, IM, or SQ

Aspart is a solution currently only approved for SQ

Glargine

All other insulins are suspensions

New Insulin: Glulisine, Detimer

D. Uses :

Type 1 diabetes

Type2 diabetes not controlled by diet exercise and weight reduction

Hyperkalemia Type 2 diabetes in combination with various oral agent ) not a FDA approved indication (

E. onset and duration of action :

Table 4. pharmacokinetics and compatibility of Various human insulin typesTable 4. pharmacokinetics and compatibility of Various human insulin types

Insulin Insulin Onset Onset Peak Peak Duration Duration Compatible Compatible when when mixed with mixed with

Short Short – – acting acting

Lispro ( Humalog) Lispro ( Humalog)

Aspart ( Novolog) Aspart ( Novolog)

Glulisine(Apidra)

Regular Regular

15 min 15 min

5-15 min5-15 min

15-20 min15-20 min

30-60 min 30-60 min

30-90 min 30-90 min

1-3 hrs1-3 hrs 0.5-2hrs0.5-2hrs

2-4 hrs2-4 hrs

3-4 hrs 3-4 hrs

3-5 hrs 3-5 hrs

5-7 hrs 5-7 hrs

NPH, Lente NPH, Lente Ultraente Ultraente NPH, Lente NPH, Lente UltraenteUltraenteNPH, Lente NPH, Lente UltraenteUltraente

InterIntermediamediate te

NPHNPH

Lente Lente

1-1.5 hrs1-1.5 hrs

1-3 hrs 1-3 hrs

4-12 hrs4-12 hrs

6-14 hrs 6-14 hrs

24+ hrs 24+ hrs

24+ hrs 24+ hrs

Regular , Regular , Lispro , Lispro , Aspart Aspart Regular , Regular , Lispro , Lispro , AspartAspart

Long Long – – acting acting

UltralenteUltralente

Glargine ( lantus )Glargine ( lantus )

detemir (Levemir)detemir (Levemir)

4-8 hrs 4-8 hrs

1-3 hrs1-3 hrs

10-30 hrs10-30 hrs

no peak no peak

36+ hrs36+ hrs

#24hrs#24hrs

#24 hrs#24 hrs

Regular , Regular , Lispro , Lispro , AspartAspartNone None

** Note : there is much interpatient variability in onset , peak and duration .

Available insulin pre- MixturesAvailable insulin pre- MixturesBrand NamesBrand Names

NPH/Regular mixture (70/30 %) NPH/Regular mixture (70/30 %) Humulin 70 / 30Humulin 70 / 30 Novolin 70/30 Novolin 70/30

NPH/ Regular Mixture ( 50/50 %) NPH/ Regular Mixture ( 50/50 %) Humulin 50/50Humulin 50/50

NPL/Lispro mixture ( 75 / 25 %) NPL/Lispro mixture ( 75 / 25 %) Humalog 75/25 Humalog 75/25

*NPL is a potamin based insulin lispro formulation that has intermediate- acting activity like NPH

F. Factor altering insulin action

1.Route of administration

2.Site of injection

3 .temperature

4. Excercices / massage

5. preparation / Mixtures

6. Dose

7. patient compliance

8.patient errors

9.Irregular diet and excesses

10.Renal function

11.stress

12.drugs

G. Stability

1.Stable at room temperature for one month ) No exposure to extreme temperature (

2. Refrigerate vials not in use and do NOT freeze

opened insulin vials in the refrigerator should be discarded after 90 days

3. Insulin prefilled in syringes is stable for 28 days with refrigeration

4. Mixture stability

Regular / NPH :

Regular / Lente or Ultralente

Lispro / NPH or Lentre or Ultralente

Glarginel/all other insulins

H. Complications of insulin therapy

1.Hypoglycemia .

a.Causes :

-Increase insulin dosage

Decrease caloric intake

Increased muscle utilization

Excessive alcohol.

b.Signs / symptoms

Termors , tachycardia , diaphorersis , confusion slurred speech , drowsiness , etc Beta- Blockers can decrease responsiveness to hypoglycemia due to blocking sympathetic warning symptoms

c. Treatment

15 –30 gm carbohydrate

follow with complex carbohydrate

Glucagen for severe patients

2.Lipohypertrophy

3.Lipoatrophy

4.Allergic reactions

5.Weight gain

1.A review of newer agents

Lispro , aspart or glulisine insulin : more closely simulates physiologic insulin secretion relative to meals .

1.Advantages :

decreases post-prandial hypoglycemia

Fewer overall occurrence of hypoglycemia , less nocturnal hypoglycemia .

Greater flexibility .

2.Disadvantages :

Risk of hypoglycemia if no meal within 15 minutes of dose

Will need to combine with a longer acting insulin for optimal BS Control

If mixed with another insulin give immediately after mixing

Hyperglycemia / ketosis may occure more rapidly if insulin delivery is interrupted

Insulin glulisine:Mixing and diluting:

When used in a pump, do not mix insulin glulisine with other insulins or with a diluent .

If glulisine is mixed with NPH human insulin, draw the glulisine into the syringe first. Make injection immediately after mixing. Do not mix glulisine with insulin preparations other than NPH.

Glargine and Detimir insulin :

1.Advantages :

provided 24 hour coverage? with a constant absorption pattern and no pronounced peak

may be beneficial in patients suffering from nocturnal hypoglycemic episodes

2.Disadvantages :

Can Not be mixed with any other insulin .

Cost

J. Insulin dosing :

1.type I patient

Average daily dose is 0.5 – 0.7 U/ kg/ day

Use lower dosages in a newly diagnosed patient

Patients should test blood glucose 4 times daily before meals and at bedtime, and occasionally at 3 AM to assess insulin dosages

Example regimens -

a.Two daily injections of a mixture of intermediate insulin ) NPH( and short – acting ) Regular , Lispro , or Aspart(

Split 2/3 AM and 1/3 PM with 2/3 of each dose as intermediate insulin and 1/3 short – acting

R/N or R/L – 0 – R/N or R/L – 0

Example : 60 kg patient total insulin requirement :

Initial regimen

Breakfast Lunch Dinner Bedtime

b. AM injection of intermediate insulin ) NPH or lente ( with short – acting ) Regular , Lispro , or Aspart ( with PM dose of short – acting and at bedtime dose of intermediate insulin

R/N or R/L – 0 –R- N or L

c.Two daily injections of an intermediate insulin

N or L – 0 – N or L – 0

d. One daily injection of a long acting or intermediate acting insulin

Glargine , N or U – 0- 0-0

e. Two daily injections of an insulin pre-mix

f. Three daily injections of a short – acting insulin ) Regular , lispro , or Aspart ( combined with a long -acting insulin at bed time.

R- R- R Glargine Or U

g. increase / decrease dose every 2-3 days until goals are met

Target FBS initially

Once the basic insulin dose is established and the patient understanding how to adjust insulin , the patient can be taught to adjust hi/ her own insulin

dose based on an algorithm or give supplemental doses and anticipatory doses (heavy exercise or heavy meals )

2. type 2 patients

-Usually intermediate acting insulin started in combination with oral agents

"BIDS" bedtime insulin / day time oral sulfonylurea

Helps suppress hepatic glucose production at night .

Starting dose :

a.FBS/ 18

b.Kg/ 10

c.10 – 15 units

Average dose often > 1 U / Kg by the time the patient is at the latter stages of the disease .

Problem Problem Time of Time of problem problem

Possible solution Possible solution

HY

PE

RG

LY

CE

MIA

HY

PE

RG

LY

CE

MIA

Fasting Fasting

Pre – lunch Pre – lunch Pre dinner Pre dinner

BedtimeBedtime

1. Evaluate causes 1. Evaluate causes 2. If the patient is on QD intermediate, then 2. If the patient is on QD intermediate, then divide into BID Dosing with 2/3 and 1/3divide into BID Dosing with 2/3 and 1/33. If the patient is on split dose BID then increase 3. If the patient is on split dose BID then increase pre- supper dose of the intermediate or move pre- supper dose of the intermediate or move that dose to laterthat dose to later

-Add/ Increase short – acting to morning dose -Add/ Increase short – acting to morning dose -Increase AM intermediate insulin dose or add -Increase AM intermediate insulin dose or add short – acting at lunchshort – acting at lunch-Add/ increase short – acting to pre dinner dose -Add/ increase short – acting to pre dinner dose

HP

OG

LY

CE

MIA

H

PO

GL

YC

EM

IA

Fasting Fasting

Pre- lunch Pre- lunch

Pre- dinner Pre- dinner

Bedtime Bedtime

-Decrease evening insulin dose ( check timing of --Decrease evening insulin dose ( check timing of -AM test and dose ) AM test and dose ) -Decrease / omit short – acting insulin dose in the -Decrease / omit short – acting insulin dose in the AM AM -Decease Am intermediating – acting dose -Decease Am intermediating – acting dose

1. Add bedtime snack1. Add bedtime snack2. decrease pre dinner dose of short –acting 2. decrease pre dinner dose of short –acting insulin insulin 3. decrease pre- dinner dose of intermediate 3. decrease pre- dinner dose of intermediate insulin if given earlier afternoon insulin if given earlier afternoon

K. Adjusting insulin doses

Think about the sliding scale when adjusting dose

L. Somogyi effect

M. Dawn phenomenon

N. Special situations

*Sick day management for insulin dependant patients

-continue insulin even if food intake is decreased .

Maintain fluid intake

Test blood glucose every 4 hours at a minimum

Test urine for ketones Administer supplemental dose of insulin according to a prescribed algorithm ) ex. 1-2 units for every 30-50 mg/dl over 120 mg/dl (

Seek medical attention if :

Urine ketones remain present and BS is > 240 mg/dl

Breathing becomes difficult Mental status changes

II. Oral Antidiabetic Agents

A.Sulfonylureas

1.Mechansim of action

Stimulate insulin release from pancereatic beta cells

2. Clinical applications

-adjunct to diet and exercise in type 2 patients

-Used in combination therapy with insulin , metformin , thiazolidinediones

or alpha – glucosidase inhibitors

3. Overall efficacy

a.HgbAIC :

b.FBG:

4. Types :

a. First generation

Acetohexamide , chlorpropamid , tolazamide , and tolbutamide

Not used commonly today duo to increase adverse effects , active metabolites , some prolonged half – lives , and increase drug interaction

b. Second generation

Glyburide , glipizde , glimepiride

5. pharmacokinetics of second generations

6. Adverse effects

Hypoglycemia

-Renal / hepatic insufficiency patients

-Elderly or malnourished patients

-Concurrent hypoglycemic drugs.

CNS

GI disturbances

Hematologic

Allergic skin reactions / photosensitivity

7. Drug interactions

a.Increased hypoglycemic effectWarfarin , azole antifungals , gemfibrozil , clofibrate , sulfonamides , MAOIs, tricyclic antidepressant , alcohol , cimetidine , aspirin and concomitant agents for diabetes .

b. Decreased hypoglycemic effect

beta – blockers , CCBs, cholestyramine , Glucocorticoides , phenytoin ,Oral contraceptives , rifampin , thiazides , niacin

8.Dosing principles

Start at low end of the dosing range , especially in the elderly

Increase dose every 1-2 weeks until maximum dosage

Exceeding the maximum dosage increases side effects, but does not decrease blood glucose

Current maximum doses now being questioned

Use cautiously in the following patients due to increasing risk of hypoglycemia

9. Treatment failure

15 % will have primary failure ) poor blood sugar control after a trial of 6-12 weeks on medication and diet (

After 5 years , ~ 50 % may experience secondary failure ) failure of medicine to work after initial good glycemic control (

B. Meglitindes ( Repaglinide – Prandin ® and Netaglinide – Starlix ®)

1 .Mechanism of action

Non – sulfonylurea moiety of glyburide

Stimulates release of insulin from the pancreatic beta cells.

2. clinical applications : -As an adjunct to diet and exercise to patients with uncontrolled type 2 diabetes

In combination with metformin to lower BS in patients who are uncontrolled by exercise , diet and either agent alone

Rapid Onset and short duration of action , so given with meals to enhance postprandial glucose utilization

3. Efficacy :

a.Hgb AIC

b.FBG:

4 .Pharmacokinetic

5. Adverse effects

Hypoglycemia

Weight gain

6 .Drug interactions

CYP450 3A4 Metabolism , so potential for interactions exist

7.Dosing principles ) see Oral antidiabetic agent table (

If HgbAIC is > 8 % start 0.5 mg repaglinide or 60 mg netaglainide with each meal .

If HgbAIC is > 8 % start 1-2 mg or 120 mg netaglinide with each meal .

Take 15-30 minutes prior to each meal

Adjust doses at weekly intervals

Instruct patients who skip a meal to skip a dose .

Instruct patient who eat an extra meal to add a dose

Metformin ( Glucophage ® or Glucophage XR ®) C.

1.Mechanism of action

Improve insulin sensitivity

Increase tissue uptake and utilization of glucose by muscle

Decrease hepatic production of glucose .

2.Clinical applications:

As an adjunct to diet in type 2 patient that are uncontrolled

In combination with sulfonylureas

-Combinations with other agents have been used

3. Efficacy :

a.HgbAIC :

b.FBG:

4. pharmacokinetics

5. Advantages

Less risk of hypoglycemia due to no insulin release

Benefit on lipids

No weight gain

6 .Disadvantages:

may cause lactic acidosis

-Contraindications to therapy:

a.Renal dysfunction

b.CHF patient , esp NYHA class III and IV

c. Alcoholics

d.Any patient at risk for lactic acidosis

GI effects

7. Drug interactions

Cimetidin , nifedipine , furosemide – all can increase metaformin levels

8. Dosing principle ) see Oral antidiabetic Agent table (

Initial dose is 500 mg po BID or 850mg Po QD , with meals to decrease side effects

Maximum dose :

Titrate dose weekly and increase by 250-500mg

D. Thiazolidnediones ( Rosiglitazone – Avandia ® and Pioglitazone – Actos ® )

1.Mechanism of action

improves cellular response to insulin W/O increasing pancreatic insulin secretion

Decrease insulin resistance

Decreases hepatic glucose production

●Results in reduction in exogenous insulin dosage when used

in combination .

●May have favorable effect on HDL

2. Clinical applications

As an adjunct to diet and exercise

In cimbination with a sulfonylurea , metformin , or insulin

3.Efficay :

a.HgbAIC :

b.FBG

4. Pharmacokinetics

5. Adverse effects

Hepatotoxicity

-Troglitazone pulled from the market secondary to hepatic fatalities

-Do not start therapy in patients with baseline LFTs> 2.5x

-Check LFTs every 2 months for the first year

-Monitor nausea vomiting , abdominal pain, fatigue , anorexia ,dark urine

Resumption of ovulation

Exacerbations of CHF

6. Drug interactions

Minimal studies available

7. Dosing principle ) see Oral antidiabetic agent table (

E. Alpha – glucosidase inhibitors ( Acarbose – precose® and Miglitol – Glyset ® (

1.Mechanism of action

Competitive reversible inhibition of intestinal alpha – glucosidase

Delays glucose absorption and lower postprandial hyperglycemia

Dose not enhance insulin secretion

No effect on weight or lipids

2. clinical applications :

As an adjunct to diet and exercise in type 2 diabetes

In combination.

3. Efficacy :

a.HgAIC

b.FBG

c.PPG

4.Pharmcokinetics

5. Adverse effect

● GI

Rashes

6 .Contraindications

7.Drug interactions

8.Dosing principles:

Titrate dosing :

-25 mg QD with the first bite of the main meal for first 7-14 days

-25mg BID week 3-4

-25mg TID week 5-12

-50mg TID ) max dose if wt > 50 kg (

-100mg TID ) max it wt > 50 kg (

F. Combination products

1.Glucovance ® : glyburide / metformin

2.metaglip ® : glipizide / metformin

3.Advadamet ® : rosiglitazone / metaformin

G. Maximizing Dosage vs. Combining Agents

Response at incremental doses .

Assess net benefit of current dose

Assess potential benefit of maximum dose

Select agent with different MOA

H. Treating Type2 diabetes under special circumstances

patients with decreased renal function

-Consider glipizide, glimerpiride, insulin , repaglinide , thiazolidinediones .

-Avoid : first generation SUs, glyburide , metformin , acarbose

patient with decreased hepatic function

-Consider : insulin , repaglinide ) cautious dosing ( , miglitol

-Avoid : thiazolidinediones , metformin , acarbose , ?glyburide , first genration Sus .

patients who are obese or gaining weight

-Consider : metformin , acarbose , miglitol

-Avoid : SUs , insulin ) unless you are at the end stage of disease (, repaglinide, ?thiazolidinediones

●patients experiencing hypoglycemia due to irregular eating patterns

-Avoid insulin and long – acting SUs.

Newer AgentsNewer Agents

DPP-4 Inhibitors:DPP-4 Inhibitors:Sitagliptin (Januvia)Sitagliptin (Januvia)

GLP-1 receptor agonist:GLP-1 receptor agonist:Exenatide (Byetta)Exenatide (Byetta)