diabetes mellitus (dm) phcl 442 - wordpress.com … · diabetes mellitus (dm) part i & ii phcl...

Diabetes Mellitus (DM)Part I & II

PHCL 416

Hadeel Al-Kofide MSc

1

Learning Outcomes

• Understand the pharmacokinetics, pharmacology, side effects, drug interactions, and proper dosing of commonly used medications for diabetes mellitus

• Construct rationale therapeutic regimens for treatment of type 1 diabetes mellitus and type 2 diabetes mellitus

• Understanding key elements in monitoring parameters in diabetic patients including hemoglobin A1C

• Know the specialized needs for the treatment of diabetes mellitus in special populations (e.g., adolescents, elderly, gestational diabetes)

2

Topics we will cover in DM

• Definition & Epidemiology• Classification• Signs & symptoms• Monitoring parameter & test to Guide

management• Principles of management:Part I: General principlesPart II: a. Insulin & its clinical applications

b. Oral anti-diabetic agents: treatment of type 2 DM

3

Definition & Epidemiology

• A syndrome caused by relative or absolute lack of insulin

• Glucose intolerance & alteration in lipid metabolism

• Diabetes is the 6th leading cause of death in U.S

• Leading causes of blindness in adults aged 20-74

• Leading causes of end – stage renal disease

• The CDC has declared an epidemic of diabetes

4CDC: Center of Disease Control & Prevention

Classification

• Type I DM

• Type II DM

• Gestational DM

5

Type I DM

• Known as ‘juvenile’, or Insulin-dependent DM (IDDM)

• Accounts for 5% - 10% of total diabetes cases

• Presenting symptoms are polydipsea, polyurea, polyphagia & weight loss

• Treatment with insulin

• Honey-moon phase

6

Classification

Type II DM

• Usually diagnosed through routine hospital visit

• Mild symptoms & gradual

• Weight loss is uncommon

• Treatment:

Exercise

Diet

Oral hypoglycemic agents

Last thing can add insulin

7

Classification

Signs & Symptoms

• The 3 Ps

• Blurred vision

• Ketoacidosis

• Fatigue

• Weight loss

8

Type I DM:More common to see ketoacidosis &

weight loss

Type II DM:Usually mild symptoms & patient may

only complain of fatigue

Monitoring Parameter & Test to Guide Management

• Urine ketone testing

• Plasma glucose

• Self monitoring blood glucose

• Glycosylated hemoglobin

9

Urine Ketone Testing

• Type I DM & GDM

• May indicate ketoacidosis

• If blood glucose > 300 mg/dl or in acute illness must test for ketones

10

Monitoring

Plasma Glucose

• Normal fasting blood glucose (FBG) 70 – 100 mg/dl

• FBG reflect hepatic glucose production (fasting state)

• Also can use random or postprandial blood glucose measurement

• To convert from mg/dl to mmol/L divide by 18

11

Monitoring

Self Monitoring Blood Glucose

• SMBG is the day-to-day monitoring choice for all patients with DM

• Problem:

Expensive

Patient must understand how to use it

12

Monitoring

Self Monitoring Blood Glucose

• Patients in whom SMBG is particularly valuable:

Type I DM: it helps patient to correlate between meals, exercise & insulin dosing with blood glucose concentration

Pregnant: Infant morbidity & mortality is associated with mother’s glucose control

Patients having difficulty recognizing hypoglycemia

Patients on intensive insulin therapy: patients who are on multiple daily dosing of insulin or insulin pump

13

Monitoring

Glycosylated Hemoglobin

• Non – enzymatic irreversible glycosylation of hemoglibine A circulating in blood, amount formed is related to degree of hyperglycemia

• Measures by % of hemoglobin

• It indicates glycemic control over 2-3 months

• Adjunct in assessing overall glycemic control

• In normal patients 4-6%

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

14

Monitoring


Hgb A1C 5% 6% 7% 8% 9% 10% 11% 12%

Average Blood glucose in mg/dl

90 120 150 180 210 240 270 300

15

Monitoring

Do not memorize just

understand the concept


• Advantages:

No need any special patient preparations (e.g. fasting)

Not subject to acute changes in insulin dosing, exercise or diet

• It does not replace the daily monitoring of blood glucose, because daily monitoring is required to adjust acute changes in glucose level and according to it plan meals & insulin dosing

16

Monitoring

Glycemic Goals According to ADA

A1C < 7%

Preprandial plasma glucose (fasting)

70–130 mg/dl (3.9–7.2 mmol/l)

Peak postprandial plasma glucose

<180 mg/dl (<10.0 mmol/l)

17

Monitoring

Glycemic Goals According to ADA

Key concepts in setting glycemic goals:

• A1C is the primary target for glycemic control

• Goals should be individualized based on:

duration of diabetes

age/life expectancy

comorbid conditions

known CVD or advanced microvascular complications

hypoglycemia unawareness

individual patient considerations

• More or less stringent glycemic goals may be appropriate for individual patients

18

Monitoring

Principles of ManagementPart I: General Principles

19

General Principles

• Goals of therapy

• Components of therapy

• Patient education

• Prevent & treatment of complications

20

Goals of Therapy

• Keep patient asymptomatic

• Prevent long term complications

• Maintain patient near euglycemia

• Achieve & maintain an appropriate body weight

• Maintain normal growth & development in children

• Enhance patient & self reliance in management of the disease

• Eliminate or minimize all cardiovascular risk factors

21

General

Principles

Components of Therapy

Diet

ExerciseDrugs

22

General

Principles

Patient Education

• Educate the patient and family about disease & treatment

• Instruct how to use insulin

• Instruct patient on method of glycemic control

• Set realistic goals

• Formulate a plan for achieving glycemic control

• Obtain agreement with the patient regarding goals & treatment & provide supportive follow up

23

General

Principles

Prevent & Treatment of Complications

• Foot care

• Annual eye exam

• Nephropathy

• Cardiovascular risk factors

24

General

Principles

Principles of ManagementPart II: A.Insulin & its Clinical Applications

25

Insulin

• Uses

• Insulin Types

• Factors affecting insulin action

• Application on insulin in clinical practice

• Complications of Insulin Therapy

26

Uses

• Type 1 diabetes

• Type 2 diabetes

• Pregnant diabetic patient

• Hyperkalemia

27

Insulin

Types of InsulinInsulin Onset Peak Duration Appearance

Short acting Lispro (Humalog)Aspart ( Novolog)Glulisine(Apidra)Regular

15 min5-15 min15-20 min30-60 min

30-90 min1-3 hrs0.5-2hrs2-4 hrs

3-4 hrs3-5 hrs

5-7 hrs

ClearClear

Clear

Intermediateacting

NPHLente

1-1.5 hrs1-3 hrs

4-12 hrs6-14 hrs

24 hrs24 hrs

CloudyCloudy

Long acting UltralenteGlargine (lantus)detemir (Levemir)

6 hrs1.5 hrs1-3 hrs

18-24 hrsFlat

36 hrs24 hrs24 hrs

CloudyClear

28

Insulin

Types of Insulin

Available insulin pre-Mixtures Brand Names

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

NPH/ RegularMixture ( 50/50 %) Humulin 50/50

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

29

Insulin

Factor Altering Insulin Action

• Route of administration

• Site of injection

• Temperature

• Exercises / massage

• Preparation / mixtures

• Dose

• Patient compliance

• Patient errors

• Irregular diet & excesses

• Renal function

• Stress

• Drugs

30

Insulin

Clinical Applications of Insulin in DM

• Basal-Bolus (Physiological) Insulin Therapy

• Methods of insulin therapy

• Initiating insulin therapy (Examples)

• Testing frequency

• Interpreting SMBG

• Fasting hyperglycemia

• Supplemental insulin doses

• Sliding scale

• Complications of insulin therapy

• Mixing insulin

31

Insulin

Basal-Bolus (Physiological) Insulin Therapy

• A physiological insulin regimen is designed to mimic normal insulin secretion as closely as possible

• Before the development of the rapid-acting insulin analogs and basal insulins, previous insulins lacked pharmacodynamic profiles that allowed one to closely simulate the basal-bolus model

• Clinicians now have more tools to mimic the pancreatic release of the hormone

32

Insulin


• In the nondiabetic individual, the pancreas secretes boluses of insulin in response to snacks & meals

• Between meals & throughout the night, the pancreas secretes small amounts of insulin that are sufficient to suppress lipolysis & hepatic glucose output (basal insulin)

33

Insulin


• Two methods have been used to achieve a similar pattern of insulin release:

1. Insulin pump therapy (previously referred to as “continuous subcutaneous infusion of insulin”)

2. Basal-bolus insulin regimens consisting of once to twice daily doses of basal insulin coupled with pre-meal doses of rapid or short-acting insulin (Multiple daily injections)

34

Insulin

Methods of Insulin Therapy

• Intensive insulin therapy (IIT):

Insulin pump

Multiple daily injections (MDI)

• Conventional method

• Example on different methods of insulin therapy

35

Insulin

Intensive Insulin Therapy

Patient selection criteria:

1. Type 1 DM, healthy, >7 yr, highly motivated & compliant individuals, willing to test blood glucose 4 times/day

2. Diabetic women who plan to get pregnant or pregnant patient

3. Patient poorly controlled on conventional therapy (including type 2)

4. Technical ability to test blood glucose

5. Intellectual ability to interpret blood glucose concentrations

6. Access to trained & skilled medical staff to direct treatment plan & provide supervision

36



When to avoid IIT?

1. Type 1 DM for more tan 15 years and controlled on conventional therapy(not all patients)

2. On beta-blockers

3. Autonomic, pituitary or adrenal insufficiency

4. Patients who are non-compliant, unable to measure blood glucose, or patients with psychiatric disorders

37



• Two major methods used to deliver IIT:

1. Insulin pump

2. MDI

38



Insulin pump:

• The most precise way to mimic normal insulin secretion

• Portable

• Delivers basal & bolus insulin doses

• New: Implantable insulin pumps

39



Multiple daily injections:

• It mimics the release of insulin from the pancreas

• Contains both basal & bolus insulin

• Insulin is given 3 times or more per day

• There are different methods to deliver MDI of insulin

40


Conventional Insulin Therapy

• Insulin is given twice daily

• It usually contains a mixture of intermediate acting & short acting insulin

41


Initiating Insulin Therapy

Clinical Situation Insulin Dose

Type 1 DM

1. Initial dose 0.5-0.8 U/kg

2. Honeymoon phase 0.2-0.5 U/kg

3. Patients with ketosis, during illnesses, during growth

1-1.5 U/kg

Type 2 DM (insulin resistance) 0.7-1.5 U/kg

42

Insulin

Initiating Insulin Therapy

43

After calculating the total daily dose (TDD) of insulin:

1. Split the dose between the regular or short acting insulin &

the intermediate or long acting insulin HOW? Either 50%

each, or 70% (the intermediate or long acting) & 30% (the

rapid or short acting insulin)

2. Then it depends in which method of insulin delivery you

will chose e.g. insulin pump, MDI or conventional method

Insulin

Examples of Different Insulin Regimens

AM Noon PM Bedtime

Reg/NPH -- Reg/NPH --

Reg/Lente -- Reg/Lente --

Lispro/NPH -- Lispro/NPH --

Lispro/Lente -- Lispro/Lente --

Aspart/NPH -- Aspart/NPH --

Aspart/lente -- Aspart/lente --

44

Method 1Why we need a short acting

here?

To cover breakfast

Why we need an intermediate acting here?

To cover lunch + basal insulin

Why we need a short acting

here?

To cover dinner

Why we need an intermediate acting here?

To cover snack + basal insulin



Disadvantages:

• Peak of NPH will be between 2-4 am causing nocturnal hypoglycemia & morning hyperglycemia (rebound hyperglycemia)

• To overcome this problem: either decrease NPH dose, or give NPH at bedtime instead of pre-dinner, why?

45

Method 1



AM Noon PM Bedtime

Reg/NPH -- Reg NPH

Reg/Lente -- Reg Lente

Lispro/NPH -- Lispro NPH

Lispro/Lente -- Lispro Lente

Aspart/NPH -- Aspart NPH

Aspart/Lente -- Aspart Lente

46

Method 2 This method is used to overcome disadvantages

of method 1



How can method 2 overcome method 1 disadvantages?

• By shifting NPH or lente dose to bedtime the peak action will occur in early morning (5-7 am) when the patient is awake & ready to eat

47

Method 2



AM Noon PM Bedtime

Reg Reg Reg NPH

Reg Reg Reg Lente

Reg Reg Reg Glargine

Reg Reg Reg Ultralente

48

Method 3



• More flexibility in meals

• If regular insulin was replaced by lispro must add with it NPH, why?

• If glargine replaces either NPH or lente the dose should be decreased by 20%

49

Method 3



AM Noon PM Bedtime

Lispro/NPH Lispro Lispro NPH

Lispro/Lente Lispro Lispro Lente

Aspart/NPH Aspart Aspart NPH

Aspart/Lente Aspart Aspart Lente

50

Method 4


Testing Frequency

Ideally patients should test their blood glucose in the following times:

• Before meals

• After meals

• Bedtime

• At 2-3 am

51

This means 8 times/day!!

Testing Frequency

But at least the patient should measure blood glucose in the following times:

• Before meals

• Bedtime

• At 2-3 am

• Patients should evaluate blood glucose level when they are not feeling well, or in case of increased physical activity, large meal, final examinations or family crisis

52

This means 4 times/day

3 times/week

Testing Frequency

• Testing blood glucose at these times corresponds with the peak action of short & intermediate acting insulin administered at different times of the day

• This enables the clinician to evaluate the effect of various insulin components on meals & to identify nocturnal hypoglycemia

• GlucoWatch?

53

Interpreting SMBG

Test Time Target Insulin Dose Target Meal/Snack

Fasting (pre-breakfast) Pre-dinner/bedtime intermediate or long acting insulin

Bedtime snack

Pre-lunch Pre-breakfast regular insulin Breakfast

Pre-dinner Pre-breakfast intermediateacting insulin or pre-lunch regular acting insulin

Lunch

Bedtime Pre-dinner regular insulin Dinner

3 am Pre-dinner intermediate acting insulin

Dinner/bedtime snack

54

Interpreting SMBG

Case 1:• J.F is a 20 year old female recently diagnosed with type I DM, she was

prescribed NPH insulin twice daily: 16 units am & 8 units PM. Her initial goal of therapy was to achieve a pre-prandial blood glucose concentration <180 mg/dl. After being on this regimen for 1 week, trends in her blood glucose concentrations were: (occasional 3 am tests was 160 mg/dl)

55

Examples

Time SMBG (mg/dl)

7 am 160-200

Noon 220-260

5 pm 130-180

11 pm 140-180

Interpreting SMBG

How to solve case 1?

• Increase TDD because her overall control is poor (increase dose to 0.6 U/kg)

• Split this dose to provide 2/3 in the morning & 1/3 at evening

• Add regular insulin to her regimen by 2:1 ratio, how?

56

Examples

Fasting Hyperglycemia

• Insufficient insulin dose

• Somogyi effect

• Dawn phenomenon

• Examples

57

Insufficient Insulin Dose

• In which there is at least 3 reading values of blood glucose are high

• The 3 am value must be high or normal (not low), why?

• Example:

7 am 19012 pm 2205 pm 2003 am 140

• Solution: increase the TDD of insulin

58


Somogyi Effect

• Also called rebound hyperglycemia; posthypoglycemichyperglycemia

• Fasting hyperglycemia but normal blood glucose at bedtime, low at 3 am with symptoms of hypoglycemia (nightmares, sweating, hunger & morning headache)

• Example:

7 am 19012 pm 1205 pm 1003 am 80

59


Somogyi Effect

• It occurs after severe hypoglycemia & its 2nd to excessive increase in glucose production by the liver that is activated by counter regulatory hormones

• The evening dose of NPH is responsible for this effect

• It is the cause of morning hyperglycemia in >10% of diabetic patients

60


Somogyi Effect

Solutions:

• Decrease NPH dose by 2-3 units, or

• Shift the pre-dinner NPH dose to bedtime (preferred than twice daily injection)

• Switch NPH to glargine, give it at bedtime & decrease the dose by 20% (remember glargine cannot be mixed with regular insulin)

61


Dawn Phenomenon

• A rise in blood glucose concentration that occurs between 4-8 am

• It is due to natural increase in growth hormone levels in the early morning (not rebound effect)

• Example:

7 am 18012 pm 1205 pm 1103 am 110

62


Dawn Phenomenon

Solutions:

• Increase evening NPH by 1-2 units

• If patient on glargine switch to something with peak as NPH or lente

• Decrease bedtime snack

63


Examples

• Example 1: Patient on NPH/Reg am & NPH/Reg pm

64


7 am 160

12 pm 130

5 pm 90

10 pm 100

3 am 60

Somogyi effect

Solution:1. Decrease evening

NPH by 1-2 units2. Give NPH at

bedtime3. Give a snack

Examples

• Example 2: Patient on NPH/Reg am & NPH/Reg pm

65


7 am 160

12 pm 130

5 pm 90

10 pm 100

3 am 100

Down phenomenon

Solution:1. Increase evening

NPH by 1-2 units2. Decrease amount of

dinner or bedtime snack

Examples

• Example 3: Patient on NPH/Reg am, Reg pm, & NPH bedtime

66


7 am 100

12 pm 60

5 pm 90

10 pm 100

3 am 110

Post-prandialhypoglycemia

Solution:1. Snack at morning2. Change from regular

to lispro3. Decrease morning

dose of regular insulin

Supplemental Insulin

• After establishing the basic dose of insulin, each patient must be educated on supplemental insulin in case of increase or decrease in blood glucose level according to SMBG

• Two methods

1. Compensatory insulin doses

2. Anticipatory insulin doses

67


Compensatory insulin doses

• These doses are used to compensate for high blood glucose levels

• It assumes that there is no unusual changes in patient’s overall diet & exercise patterns

• Given as regular or short acting insulin (lispro& aspart are preferred due to shorter duration of action)

68


Anticipated insulin doses

• Prescribed in anticipation of an immediate event that is likely to alter a patient’s response to insulin

• This include an unusual large or small meal or exercise

• Increase lispro, aspart or regular insulin by 1 unit for each additional 15 g of carbohydrates

• Decrease lispro, aspart or regular insulin by 1 unit for smaller meals

69

Sliding Scale

• Algorithmic method for adjusting doses of short or regular acting insulin according to blood glucose test results

• Used for hospitalized patients in which their insulin requirements may vary significantly due to stress (infection, surgery or acute illnesses), inactivity or variable caloric intake

• Blood glucose levels are measured every 4 hours if given SC, & every hour if given IV

70

Sick Day Management

1. Continue insulin even if food intake is decreased

2. Maintain fluid intake

3. Test blood glucose every 4 hours at a minimum

4. Test urine for ketones

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

6. Seek medical attention if : Urine ketones, blood glucose > 300 mg/dl or mental status changes

71

Complications of Insulin Therapy

1. Hypoglycemia

• Causes:

Increase insulin dosage

Decrease caloric intake

Increased muscle utilization

Excessive alcohol

72


• Signs / symptoms

Termors, tachycardia, diaphorersis, confusion slurred speech, drowsiness, etc

Beta- Blockers can decrease responsiveness to hypoglycemia due to blocking sympathetic warning symptoms

• Treatment

15 –30 gm carbohydrate follow with complex carbohydrate

Glucagon for severe patients

73


2. Lipohypertrophy

3. Lipoatrophy

4. Allergic reactions

5. Weight gain

74

Mixing InsulinMixture Proportion Comments

Regular + NPHAny

proportion

The pharmacodynamic profiles of regular & NPH insulin are

unchanged when premixed & stored for up to 3 months

Rapid-acting + NPHAny

proportion

Rapid-acting insulin and NPH should be mixed just before use (within 15

minutes)

Insulin glargine & detemirDo not mix with other

insulins

Pharmacodynamics could be modified

75

Principles of ManagementPart II: B. Oral antidiabetic Agents

(Treatment of Type II DM)

76

Treatment of Type 2 DM

• Types of noninsulin antidiabetic agents available

• How to treat type 2 patients?

• Treating type 2 patients under special circumstances

77

Anti-Diabetic Agents

• Types of Oral antidiabetic agents available

1. Alpha – glucosidase inhibitors

2. Biguanides

3. Non-sulfonylurea insulin secretagogues (Meglitindes)

4. Sulfonylureas

5. Thiazolidnediones

6. New agents

78



79

Agent MechanismFDA

IndicationsAdverse Effects

Comments

Delayers of Carbohydrate Absorption

α-GlucosidaseinhibitorsAcarboseMiglitol

Slow absorption of carbohydrates

Monotherapy; combined with SFUs

•GI: flatulence, diarrhea

•Elevations in LFTs seen in doses >50

mg TID of acarbose

•LFTs should be monitored every 3 months during the

first year & periodically•Because miglitol is not

metabolized, monitoring of LFTs is not required

•Titrate dose slowly to minimize GI effects

•No hypoglycemia or weight gain



80

Agent MechanismFDA


Comments

Insulin-Augmenting Agents

SulfonylureasStimulate insulin

secretion.May decrease

hepatic glucose output & enhance peripheral glucose

utilization

Monotherapy; combined with

metformin; combined with insulin

(glimepiride)

•Hypoglycemia, especially long-acting agents•Weight gain

• Rash•Hepatotoxicity

•Very effective agents, Some can be dosed once

daily•Rapid onset of effect (1

wk)


Sulfonylureas

First generation

• Acetohexamide, chlorpropamid, tolazamide, & tolbutamide

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

Second generation

• Glyburide, glipizde, & glimepiride

• 100 times more potent than first generation

81


82

Agent MechanismFDA


Comments

Insulin-Augmenting Agents

Nonsulfonylureasecretagogues

RepaglinideNateglinide

Stimulate insulin

secretion

Monotherapy; combined with

metformin or TZD

Hypoglycemia, weight gain

•Take only with meals•If a meal is skipped, skip a

dose•Flexible dosing with lifestyle•Safe in renal & liver failure

•Rapid onset



83

Agent MechanismFDA


Comments

Insulin Sensitizers

BiguanidesMetformin

(Glucophage)↓ Hepatic glucose

output;↑ Peripheral

glucose uptake

Monotherapy; combined with SFU and/or TZD; or with

insulin

•GI: nausea, cramping, diarrhea

•Lactic acidosis (rare)

•Titrate dose slowly to minimize GI effects

•No hypoglycemia or weight gain

•Weight loss possible•Mild reduction in

cholesterol•Do not use in patients with renal or hepatic dysfunction or CHF requiring treatment



84

Agent MechanismFDA


Comments

Insulin Sensitizers

Thiazolidined-ionesRosiglitazone Pioglitazone

Enhance insulin action in periphery;

increase glucose utilization by

muscle & fat tissue; decrease hepatic glucose output

Monotherapy; combined with SFU, or

insulin

•Mild anemia; fluid retention & edema

•Weight gain•Fractures (in

women)

•Can cause or exacerbate CHF

•Not used in symptomatic heart failure or class III or IV

CHF•Rosiglitazone may increase

risk of MI•Increased risk of fractures

in women•LFTs must be measured at

baseline & periodically•Slow onset (2–4 wk)



• Newer agents:

• GLP-1 receptor agonists: Exenatide

• DPP-4 Inhibitors: Sitagliptin

• Amylin mimetic: Pramlintide

85



• How to treat type 2 patients?

Monotherapy (step 1)

Failure of monotherapy

Combination therapy with oral agents (step 2)

Combination therapy with insulin (step 3)

86

Monotherapy (Step 1)

• Usually start with metformin unless contraindicated

• Almost all other agents can be used as monotherapy initially, just look at the patients condition

• Often acarbose is eliminated from consideration as first line agent because slow titration is required to minimize GI effects

87

Treatment of Type 2 DM: How to treat?

Failure of Antidiabetic Monotherapy

• When SFUs were used exclusively for oral monotherapy (before other oral agents were available), loss of glycemic control, called secondary failure, was fairly common, 5% to 10% /year in patients who initially were well controlled on these agents

• After 5 years, ~ 50 % may experience secondary failure

• Monotherapy failure is characterized by poor glucose control that occurs after a 1-month to a several-year of good response

88



• The cause of failure may be related to:

Progressive pancreatic failure

Poor compliance with diet, exercise, or medications

Exogenous diabetogenic factors such as obesity, illness, or drugs that induce hyperglycemia

89



• Management:

Identifying & correcting any diabetogenic factors & altering her drug therapy

When failure to any oral agent occurs, one should always add another agent rather than switch to another

Many combinations of antidiabetic agents can be used but chose ones with different mechanisms (example?)

Maintain the current agent & add another rather than to change to two new medications

90


Combination Therapy (Step 2)

• When agents from different antidiabetic classes are combined, their effects are essentially additive

• With the availability of many antidiabetic agents, there is no one best combination therapy

• The choice of therapy should take into account the patient's organ function, amount of HbA1c lowering required to reach an individual's goal, possible adverse effects of a particular drug or drug combination, cost, & patient preference

91


Combination Therapy (Step 3)

• When a combination of oral agents fails, practitioners often add a third agent before considering insulin

• Although this is tempting, depending on a patient's current level of glycemic control, this practice only delays insulin therapy, which is likely to be required to achieve HbA1c goals

92


Combination Therapy (Step 3) +Insulin

• Most patients with type 2 diabetes eventually require insulin

• The combined use of insulin & oral agents can be considered at both steps 2 and 3 in the ADA algorithm

• A bedtime insulin is added to the patient regimen

93



• The traditional approach to adding insulin therapy to an oral agent (i.e., a sulfonylurea) was called BIDS therapy (bedtime insulin, daytime sulfonylurea)

• Now, with many available antidiabetic options, bedtime basal insulin (using NPH, glargine, or detemir) can be added to single or combination (usually only two) oral agent therapy

94



• Studies seem to confirm potential advantages of metformin over sulfonylureas when used in combination with insulin

• These include its favorable effects on the lipid profile, insulin concentrations, & lack of weight gain

• The risk for hypoglycemia may also be lower with metformin than with combined use of sulfonylurea

• Use of a TZD with insulin is effective in reducing insulin doses & HbA1c. However, the disadvantage with this combination is weight gain and significant edema (~15%)

95



• The initial dose of insulin will be low 0.2 unit/kg of NPH, insulin glargine, or insulin detemir at bedtime

• The basal insulin dose can be increased by 2 units every 3 days until the FPG is in a target range (70–130 mg/dL)

• If there is no improvement in glycemic control after 3 months, patient should be converted to multiple daily insulin injections

96



• An alternative is to discontinue all oral agents & begin insulin monotherapy using methods similar to type 1 patients

• This option is rational based on the fact that patients are likely to require insulin therapy because of progressive β-cell failure

• Insulin monotherapy may be less expensive & easier to assess than combination oral agents plus insulin therapy

• Many clinicians use single doses of basal insulin in combination with oral agents as a bridge to eventual insulin monotherapy, especially for those patients unwilling to adhere to multiple daily insulin injections

97


Treating Type 2 DM Under Special Circumstances

Circumstances Avoid Consider

Patients with decreased renal function

AcarboseLong-acting SFUs (e.g.,

glyburide)Metformin

GlipizideGlimepiride

InsulinGlinides (Repaglinide/

nateglinide)Thiazolidinediones

Patients with impaired liver function

AcarboseMetformin

ThiazolidinedionesSFUs (severe liver

dysfunction)

InsulinRepaglinide

Miglitol

Patients who are obese or gaining excessive weight

InsulinSulfonylureasRepaglinide

Thiazolidinediones

AcarboseMiglitol

Metformin98

Treating Type 2 DM Under Special Circumstances

Circumstances Avoid Consider

Patients with preexisting edema

ThiazolidinedionesSFUs

Glinides

Patients with heart failureThiazolidinediones

Metformin

SFUsGlinidesInsulin

Patients experiencing hypoglycemia due to

irregular eating patterns

InsulinLong-acting SFUs

AcarboseMetformin

Repaglinide/nateglinideThiazolidinediones

99

Principles of ManagementTreatment Algorithm for Type 2 DM

100

Start Treatment for Type 2 DM

101

References

• Applied Therapeutics: The Clinical Use of Drugs, 9e

• Pharmacotherapy: A PathophysiologicApproach, 7e

• Standards of Medical Care in Diabetes—2010: American Diabetes Association Guideline

102

Thank you

103

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