Diabetes Mellitus Chapter 77

Pharmacotherapy: A Pathophysiologic Approach The McGraw-Hill Companies 1

AbbreviationsACE: angiotension-converting enzymeADA: American Diabetes AssociationALLHAT: Antihypertension and Lipid-Lowering Treatment to Prevent Heart Attack TrialALT: alanine aminotransferaseBMI: body mass indexCAD: coronary artery diseaseCHD: coronary heart diseaseCHF: congestive heart failureCV: cardiovascularCOPD: chronic obstructive pulmonary diseaseCV: cardiovascular CYP450: cytochrome P450DCCT: Diabetes Control and Complications TrialDM: diabetes mellitus

22

AbbreviationsDPP IV: dipeptidyl peptidase IVDREAM: Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (study)

FPG: fasting plasma glucose

GDM: gestational diabetes mellitus

GIP: glucose-dependent insulin-releasing peptide

GLP-1: glucagon-like peptide-1

HbA1c: hemoglobin A1c

HDLC: high-density lipoprotein cholesterol

IFG: impaired fasting glucose

IGT: impaired glucose toleranceLADA: latent autoimmune diabetes in adults

3

AbbreviationsLDLC: low-density lipoprotein cholesterolMI: myocardial infarctionNCEP-ATP: National Cholesterol Education Program Adult Treatment PanelNHANES III: The Third National and Nutrition Evaluation SurveyNPH: neutral protamine hagedornNYHA: New York Heart Association OGTT: oral glucose tolerance testPAI-1: activator-1 plasminogen-inhibitor

PCOS: polycystic ovary syndrome

PROactive Prospective Pioglitazone Clinical Trial in Macrovascular Events

SMBG: self-monitored blood glucose

SUR: sulfonylurea receptor

TZD: thiazolidinedione

UKPDS: United Kingdom Prospective Diabetes Study4

Overview Definition & classification

Diagnosis

Goals of therapy

Lifestyle modifications

Treatment

Insulin therapy

Microvascular & macrovascular complications

55

6

Diabetes Mellitus (DM) Group of metabolic disorders characterized by

hyperglycemia resulting from either or both:

insufficient insulin secretion

resistance to the action of insulin

Abnormalities in carbohydrate, fat, protein metabolism

Results in chronic complications

microvascular

retinopathy, neuropathy, diabetic nephropathy

macrovascular

coronary artery disease, peripheral artery disease, stroke

6

7

Insulin promotes synthesis (from circulating nutrients) and storage of

glycogen, triglycerides, and protein in its major target tissues: liver, fat, and

muscle. The release of insulin from the pancreas is stimulated by increased

blood glucose, incretins, vagal nerve stimulation, and other factors.

Effects of Insulin on Various Tissues

8

Adipose Tissue

Increased glucose entry

Increased fatty acid synthesis

Increased glycerol phosphate synthesis

Activation of lipoprotein lipase

Inhibition of hormone-sensitive lipase

Increased K+ uptake

Muscle

Increased glucose entry

Increased glycogen synthesis

Increased amino acid uptake

Increased protein synthesis in ribosomes

Decreased release of gluconeogenic amino acids

Increased ketone uptake

Increased K+ uptake

Liver

Decreased ketogenesis

Increased protein synthesis

Increased lipid synthesis

Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysis

General

Increased cell growth

9

Insulin stimulates hepatic glucose storage as glycogen; in adipose tissue as triglycerides; and amino acid storage

in muscle as protein; it also promotes utilization of glucose in muscle for energy. These pathways, which also are

enhanced by feeding, are indicated by the solid blue arrows. Insulin inhibits the breakdown of triglycerides,

glycogen, & protein and conversion of amino acids to glucose (gluconeogenesis), as indicated by the white

arrows. These pathways are increased during fasting and in diabetic states. Conversion of amino acids to glucose

& glucose to fatty acids occurs primarily in the liver.

10

11

Diabetes Mellitus ~ 23.6 million Americans have DM only 17.9 million have been diagnosed

Economic burden of DM ~$174 billion in 2007

Leading cause of blindness in adults ages 20 to 74 years

Leading contributor to kidney failure

Accounts for ~71,000 lower-limb amputations annually

~2/3 of deaths are caused by a CV event in DM patients

11

Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008.

12

National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes mellitus in United States by age (≥20 years of age) 1988-1994 and 1999-2002 13

14National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes mellitus in United States by age (≥20 years of age) 1988-1994 and 1999-2002

Diabetes Classification Majority of diabetics classified in 2 categories:

type 1: absolute deficiency of insulin

type 2: presence of insulin resistance with reduced insulin secretion

Gestational diabetes

triggered by stress of pregnancy

Other specific types:

infections, drugs, endocrinopathies, pancreatic destruction, genetic defects

1515

Type 1 DM Autoimmune destruction of pancreatic β-cells

~90% of patients have markers of immune β-cell destruction at diagnosis

children & adolescents often have rapid β-cell destruction & present with ketoacidosis

may occur at any age

Known as latent autoimmune diabetes in adults (LADA)

slowly progressive

sufficient insulin secretion to prevent ketoacidosis for many years

1616

Type 1 DM Pathogenesis 1. Preclinical period

immune markers present

β-cell destruction

2. Hyperglycemia

80 to 90% of β-cells destroyed

3. Transient remission

honeymoon phase

4. Established disease

1717

18

Type 1 DM Pathogenesis

Type 2 DM Insulin resistance, relative lack of insulin secretion

Usually presents with cluster of abnormalities known as metabolic syndrome:

abdominal obesity

hypertension

dyslipidemia

elevated PAI-1 levels

Increased macrovascular complication risk

1919

20

NCEP ATP III: Components of the Metabolic Syndrome (> 3 for diagnosis)

aOverweight/obesity associated with insulin resistance & metabolic syndrome. The presence of abdominal obesity more highly correlated with metabolic risk factors than elevated body-mass index (BMI). bSome male patients can develop multiple metabolic risk factors when waist circumference is only marginally increased; benefit from life-style changes.

Risk Factor Defining Level

Abdominal obesitya

Men (waist circumference)b > 102 cm (> 40 in.)

Women > 88 cm (> 35 in.)

Triglycerides > 1.7 mmol/L (> 150 mg/dL)

HDL cholesterol

Men < 1.0 mmol/L (< 40 mg/dL)

Women < 1.3 mmol/L (< 50 mg/dL)

Blood Pressure ≥ 130/≥ 85 mmHg

Fasting glucose > 6.1 mmol/L ( > 110 mg/dL)

20

21

Pathogenesis

Whole body glucose disposal, a measure of insulin resistance, is reduced 40% to 50% in obese nondiabetic and lean type 2 diabetic individuals. Obese diabetic individuals are slightly more resistant than lean diabetic patients.

22

PathogenesisThe relationship between fasting plasma insulin and fasting plasma glucose in 177 normal weight individuals. Plasma insulin and glucose increase together up to a fasting glucose of 140 mg/dL. When the fasting glucose exceeds 140 mg/dL, the β cell makes progressively less insulin, which leads to an overproduction of glucose by the liver and results in a progressive increase in fasting glucose.

23

Pathogenesis

The loss of the incretin effect in type 2 diabetes mellitus. The plasma insulin responses to oral and intravenous glucose in nondiabetic subjects (left figure), compared to patients with diabetes (right figure).

Screening Type 1

not recommended

low prevalence, acute symptoms

Type 2

fasting plasma glucose (FPG) recommended

alternative: oral glucose tolerance test (OGTT)

more costly, less convenient, less reproducible

HbA1c not recommended

no gold standard assay

useful in monitoring glycemic control after diagnosis

2424

Glucose Tolerance Test

25

Blood glucose curves of a

normal and a diabetic person

after oral administration of 1 g

of glucose/kg body weight.

Note the initial raised

concentration in the fasting

diabetic.

A criterion of normality is the

return of the curve to the initial

value within 2 hours.

26

Type 2 DM Screening

aBMI > 85th percentile for age & sex, > 85th percentile weight for height, or > 120% of ideal weight for height

bFamily history of DM2 in 1st or 2nd degree relative; high risk ethnic group; signs of insulin resistance; maternal history of gestational diabetes during child’s gestation

c BMI ≥ 25kg/m2

ADA Type 2 Diabetes Screening Recommendations

Children & Adolescents Every 3 years at age 10 or onset of puberty if overweighta with two additional risk factorsb

Adults Every 3 years in adults ≥ 45 years of age or earlier if overweightc & additional risk factors present

American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.

BMI ≥ 25 Physical inactivity 1st degree relative with DM High risk ethnic group

(Latino, African American, Native American, Asian American, Pacific Islander)

IFG, IGT HTN: ≥ 140/90 mmHg or

on therapy for HTN

CV disease HDL < 35 mg/dL Triglycerides > 250 mg/dL Delivery of > 9 lb baby History of GDM Insulin resistance acanthosis nigricans,

severe obesity Polycystic ovary syndrome

27

Type 2 DM Risk Factors

American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.

Screening for Gestational DM Risk assessment at 1st prenatal visit

Screen high risk women as soon as possible

family history of DM

history of GDM

marked obesity

presence of glycosuria

diagnosis of PCOS

If initial screening negative, retest high risk women at 24 to 28 weeks gestation

2828American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.

Screening for Gestational DM Low-risk patients do not require screening

must meet the following criteria:

age < 25 years

normal weight

member of ethnic group with low DM incidence

no known diabetes in 1st degree relatives

no history of abnormal glucose tolerance

no history of poor obstetrical outcome

Average risk

screen at 24 to 28 weeks gestation

29American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.

One-step approach

diagnostic 3 hr 100 g OGTT

Two-step approach

initial screen: plasma or serum glucose measured 1-hour after 50 g glucose load

glucose threshold: ≥ 140 mg/dL (~80% sensitivity); ≥ 130 mg/dL(~90% sensitivity)

diagnostic test: 100 g OGTT in women who exceed initial screen threshold

Diagnosis of GDM requires 2 of the following:

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fasting: ≥ 95 mg/dL

1 hour: ≥ 180 mg/dL



Screening for Gestational DM

31

Diagnosis Normal FPG < 100 mg/dL

2 hr postload plasma glucose < 140 mg/dL

Impaired fasting glucose FBG = 100 to 125 mg/dL

Impaired glucose tolerance 2 hr postload plasma glucose = 140 to 199 mg/dL

Diabetes mellitus FPG ≥ 126 mg/dL

2 hr postload plasma glucose ≥ 200 mg/dL

32

Diagnosis

In absence of unequivocal hyperglycemia: confirm on different day

a Fasting: no caloric intake for at least 8 hoursb Classic symptoms: polyuria, polydipsia, unexplained weight lossc Causal: any time of day without regard to last meald Oral glucose tolerance test: equivalent to 75-g anhydrous glucose in H2O; not recommended for routine clinical use

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

ADA Criteria for DM Diagnosis

1 Fastinga plasma glucose (FBG) ≥ 126 mg/dL

2 Symptoms of diabetesb & casualc plasma glucose ≥ 200 mg/dL

3 2-hour plasma glucose ≥ 200 mg/dL during OGTTd

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Characteristic Type 1 DM Type 2 DM

Age < 30 yearsb > 30 yearsb

Onset Abrupt Gradual

Body habitus Lean Obese or history of obesity

Insulin resistance Absent Present

Autoantibodies Often present Rarely present

Symptoms Symptomaticc Often asymptomatic

Ketones at diagnosis Present Absentd

Need for insulin therapy Immediate Years after diagnosis

Acute complications Diabetic ketoacidosis Hyperosmolar hyperglycemic state

Microvascular complications at diagnosis

No Common

Macrovascular complications at or before diagnosis

Rare Common

34

Clinical Presentation of Diabetesa

aClinical presentation can vary widely. bAge of onset for type 1 DM is generally < 20 years of age but can present at any age. The prevalence of type 2 DM in children, adolescents, and young adults is increasing. This is especially true in ethnic and minority children. cType 1 can present acutely with symptoms of polyuria, nocturia, polydipisia, polyphagia, weight loss. dType 2 children and adolescents are more likely to present with ketones but after the acute phase can treated with oral agents. Prolonged fasting can also produce ketones in individuals.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

35

HbA1c (Hemoglobin A1c): gold standard for monitoring glycemic control

HbA1c reflects glucose levels for the previous 2 to 3 months

Treatment Goals

Glycemic Goals

Biochemical Index ADA ACE/AACE

Hemoglobin A1c < 7% ≤ 6.5 %

Preprandial plasma glucose 70-130 mg/dL < 110 mg/dL

Postprandial plasma glucose < 180 mg/dL < 140 mg/dL

36

Reduce risk for microvascular & macrovascular disease complications

Ameliorate symptoms

Reduce mortality

Improve quality of life

36

ADA, American Diabetes Association; ACE, American College of Endocrinology, AACE, American Association of Clinical Endocrinologists


Clinical Controversy Results of the ACCORD, ADVANCE, & VADT trials

suggest less intensive glucose lowering may be appropriate for some patients

advanced age

major comorbidities

presence of microvascular/macrovascular complications

37

Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. The advance collaborative group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358;2560-2572. Duckworth W, Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med. 2009;360:129-139

Recommendations

Screening for diabetes

Screen overweight at 45 years old, repeat at 3-year intervalsScreen with fasting plasma glucose or 2-hour 75-g OGTT

Monitoring Home blood-glucose monitoring is needed if on insulinSubjects on other therapeutic interventions, including oral agents may need home blood glucose monitoringQuarterly HbA1c in individuals not meeting glycemic goals, twice yearly in individuals meeting glycemic goals should be performed

Glycemic goals HbA1c goal for patients in general is < 7%HbA1c goal for individuals is as close to normal (< 6%) as possible without significant hypoglycemia

Medical nutrition therapy

Weight loss is recommended for all insulin-resistant/overweight or obese individualsSaturated fat should be < 7% of total caloriesMonitoring carbohydrate intake by carbohydrate counting or exchanges is recommended. Glycemic index can give modest benefits over total carbohydrate intake. Low-carbohydrate diets (< 130 g of carbohydrate) not currently recommended as long-term effects are unknown

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ADA Evidence-Based Recommendations

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Treatment Recommendations

Physical activity 150 min/wk of moderate intensity exercise is recommended or 90 minutes of vigorous exercise per week Resistance-train large muscle groups 3 times per week

Blood pressure Systolic blood pressure should be treated to < 130 mm HgDiastolic blood pressure should be treated to < 80 mm Hg

Nephropathy Type 1 DM with any degree of albuminuria - ACE inhibitorType 2 DM with microalbuminuria - ACE inhibitor or angiotensinreceptor blockerType 2 DM with macroalbuminuria - angiotensin receptor blocker

Dyslipidemia The primary goal is an LDL < 100 mg/dLIf 40 years of age or older, statin therapy to reduce LDL 30–40%, regardless of baseline LDL, is recommendedLDL < 70 mg/dL optional goal in individuals with overt cardiovascular (CV) diseaseTriglycerides should be lowered to < 150 mg/dLIncrease HDL to > 40 mg/dL in men and > 50 mg/dL in women

39

ADA Evidence-Based Recommendations

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Self-Monitoring of Blood Glucose Type 1:

necessary to achieve near-normal blood glucose levels

used to assess for hypoglycemia

Type 2:

frequency unresolved

improves glycemic control when patients are using insulin

40

Clinical Controversy Few studies show significant glycemic improvements

with frequent SMBG for type 2 DM patients not using insulin

1 study shows average HbA1c reduction of 0.4% with frequent testing

others studies show no change

Patients must be empowered to change lifestyle, medications in response to SMBG to see benefit

money wasted on testing supplies if patients do not change therapeutic regimen in response to testing results

41Welschen LMC, Bloemendal E, Nijpels G, et al. Self-monitoring of glucose in patients with type 2 diabetes who are not using insulin. Diabetes Care 2005;28:1510–1517.

42

Nonpharmacologic Therapy Medical nutrition therapy

recommended for all DM patients

provides optimal metabolic outcomes

prevents/treats chronic DM complications

Regulates insulin administration with a balanced diet to achieve/maintain a healthy weight

carbohydrate counting or exchanges

Promotes weight loss to overweight patients

caloric restriction

Nonpharmacologic Therapy Exercise

improves insulin resistance, glycemic control

reduces CV risk

helps with weight loss or maintenance

improves well-being

Patients without contraindications

> 150 min/week moderate-intensity aerobic exercise

resistance training for 30 min 3 times/week

Start exercise slowly in previously sedentary patients

43

Nonpharmacologic Therapy Evaluation for exercise

routine CAD screening not recommended for asymptomatic patients

high risk patients may need CV evaluation

complications can require activity restrictions

retinopathy: vigorous aerobic or resistance exercise contraindicated

peripheral neuropathy: non-weight bearing activities only

autonomic neuropathy: cardiac investigation prior to starting any activity

44

Pharmacotherapy Insulin

Exenatide

Pramlinitide

Sulfonylureas

Meglitinides

Biguanides

Thiazolidinediones (TZDs)

α–glucosidase inhibitors

DPP-IV inhibitors

45

Insulin Anabolic & anticatabolic hormone

Necessary for carbohydrate, protein & fat metabolism

Required for all type 1 DM patients

Recommended for type 2 DM patients that do not achieve glycemic control with PO antidiabetic agents

Insulin strengths in the US

100 units/mL (U-100)

500 units/mL (U-500)

only available in regular insulin

46

Insulin Originally derived from bovine & procine pancreas

All human insulin in the US now made exclusively by recombinant DNA (rDNA) technology

Recombinant insulin analogs also available via modification of human insulin molecules

synthesized to overcome problems of human insulin

onset of action

duration of action

absorption

4747

Insulin Basal Insulin

mimics normal pancreatic insulin secretion with constant levels

suppresses glucose production in the fasting & postabsorptive period

Bolus Insulin

mimics spikes of physiologic secretion insulin after eating

48

49

Insulin PharmacokineticsType of Insulin

Onset (Hours)

Peak (Hours)

Duration (Hours)

Maximum Duration (Hours)

Appearance

Rapid-acting

Aspart 15–30 min 1–2 3–5 5–6 Clear

Lispro 15–30 min 1–2 3–4 4–6 Clear

Glulisine 15–30 min 1–2 3–4 5–6 Clear

Short-acting

Regular 0.5–1.0 2–3 3–6 6–8 Clear

Intermediate-actinga

NPH 2–4 4–6 8–12 14–18 Cloudy

Long-acting

Detemir 2 hours 6–9 14–24 24 Clear

Glargine 4–5 — 22–24 24 Clear

NPH, neutral protamine Hagedorn.aLente and ultralente insulin has been discontinued.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Long-Acting Insulin Insulin glargine, insulin detemir

mimic basal insulin secretion

slow action over 24 hours

lower risk of hypoglycemia

daily or BID dosing

50

Long-Acting Insulin Mechanism of action

insulin glargine

low solubility at neutral body pH, microprecipitates form at injection site & are slowly released

insulin detemir

forms a fatty acid chain that binds interstitial albumin at injection site; causes prolong absorption

dissociated detemir molecules enter circulation & again bind albumin causing further delay in distribution

5151

Intermediate-Acting Insulin NPH

mimics basal insulin secretion

administered twice daily

52

Short-Acting Insulin Regular insulin

bolus insulin to control post-prandial spikes

inject 30 to 60 min prior to meals due to onset of action

may cause postprandial hyperglycemia due to rapid increase in blood glucose after meals & delayed onset of action

late hypoglycemia due to prolonged duration of action

53

Rapid-Acting Insulin Insulin lispro, insulin aspart, insulin glulisine

recombinant insulin analogs

bolus insulin

faster absorption & shorter duration of action than regular insulin

administer 5 to 15 min AC

superior postprandial glucose lowering of glucose compared to regular insulin

54

55

Structure of human proinsulin and some commercially available insulin analogs. Insulin is shown

as the shaded (darker color) peptide chains, A and B. Differences in the A and B chains and

amino acid modifications for insulin aspart, lispro, and glulisine are noted

56

Extent and duration of action of various types of insulin as indicated by the glucose infusion

rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of

action shown are typical of an average dose of 0.2–0.3 U/kg; with the exception of insulin

lispro, aspart, and glulisine, duration increases considerably when dosage is increased.

Trade/Generic Name Administration Options Room Temperatureb

Expiration

Premixed insulin analogs

Humalog Mix 75/25 (75% neutral protamine lispro, 25% lispro)

Vial, prefilled pen Vial: 28 days; pen: 10 days

NovoLog Mix 70/30 (70% aspart protamine suspension, 30% aspart)

Vial, prefilled pen, 3-mL pen cartridge

Vial: 28 days; others: 14 days

Humalog Mix 50/50 (50% neutral protamine lispro/ 50% lispro)

3-mL pen 10 days

NPH-regular combinations

Humulin 70/30 Vial, prefilled pen Vial: 28 days; pen: 10 days

Novolin 70/30 Vial, pen cartridge, InnoLetc

Vial: 30 days; others: 10 days

Humulin 50/50 Vial 28 days

57

Pre-mixed Insulin Products


CInnoLet: A prefilled insulin pen with a "kitchen timer" type of dial for determining the number of insulin units. Can be useful in patients with impaired eyesight or dexterity.

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Insulin Dose Individualized dosing

Type 1 DM: average daily requirement 0.5-0.6 units/kg

basal insulin 50%

mealtime insulin 50%

Type 2 DM: doses vary depending on degree of insulin resistance

0.7 to 2.5 units/kg or more

58

59

Insulin Storage Refrigerate unopened injectable insulin

do not freeze

Use unopened insulin by manufacturer’s expiration date

Opened insulin expire based on type & delivery device

may be kept at room temperature (15-30˚C or 59-86˚F)

Inspect before use for clumping, precipitates, discoloration, etc.

59

Human Inhaled Insulin Withdrawn from the market due to poor sales

Studied in type 1 & type 2 DM patients

Formulated to reach alveolar space

Onset & peak similar to rapid-acting insulin

Duration of action similar to regular insulin

Blister packets of human insulin powder

1 mg: ~3 units of subcutaneously insulin

3 mg: ~8 units of subcutaneously insulin

administered via inhaler (complicated to use)

60

Exenatide Synthetic analog of amino acid peptide exendin-4

isolated from Gila monster saliva

Mechanism similar to human GLP-1

enhances insulin secretion

suppresses postprandial glucagon when blood glucose elevated; reduces hepatic glucose production

Slows gastric emptying, reduces food intake, promotes weight loss

Unlike GLP-1, exenatide does not increase gastric secretions

61

Exenatide Indication: adjunctive therapy for type 2 DM

Not recommended in end-stage renal disease or dialysis patients

prolongs t½

increases incidence of GI side effects

Adverse effects:

nausea, vomiting, diarrhea

may improve over time

dose-related, slowly titrate dose

62

Exenatide Postmarketing cases of acute pancreatitis

May delay absorption of other medications: slow gastric emptying

not recommended for patients with gastroparesis

Dose

start with 5 mcg BID

may titrate to 10 mcg BID when tolerated

inject subcutaneously within 60 min of morning & evening meals

63

64

Exenatide Average HbA1c reduction ~0.9%

Significantly decreases postprandial glucose excursions

Modest effects on FBG

Average weight loss in studies: 1 to 2 kg over 30 weeks

long-term, open-labeled trials show continued weight loss for at least 2.5 years with 10 mcg BID dose

Improvements in triglycerides & HDL seen with exenatide 10 mcg BID

64

65

Pramlintide Adjunctive therapy for patients using insulin

Synthetic analog of amylin

neurohormone co-secreted from β-cells with insulin

Suppresses postprandial glucagon secretion

Reduces food intake

Slows gastric emptying

66

Pramlintide Subcutaneous injection in abdomen or thigh

variable absorption with arm injection

Adverse effects:

GI most common

nausea, vomiting, anorexia

may decrease over time

dose-related, slowly titrate dose upwards

May delay absorption of other medications; slow gastric emptying

67

Pramlintide Reduce preprandial insulin dose 30 to 50% at

pramlintide initiation

Basal insulin dose may be reduced if FBG close to goal

Dosing

type 2: 60 to 120 mcg prior to meals

type 1: 15 to 60 mcg prior to meals

2.5 units on 100 units/ml insulin syringe = 15 mcg of pramlinitide

68

Pramlintide Average HbA1c reduction 0.4 to 0.6%

Decreases prandial glucose excursions

Little effect of FBG concentrations

Main advantage in type 1 DM is that it stabilizes wide postprandial glycemic swings

Average weight loss in controlled trials: 1 to 2 kg

69

Sulfonylureas Enhance insulin secretion

bind SUR receptors on pancreatic β cells

results in suppressed hepatic glucose production

Classification: 1st & 2nd generation

differences in potency, adverse effects, serum protein binding

no therapeutic superiority among agents

Glipizide preferred over glyburide

glyburide requires adjustment for renal dysfunction; higher risk of hypoglycemia

SulfonylureasGeneric Name Dose

(mg)Recommended Starting Dosage

(mg/day)

Equivalent Therapeutic Dose (mg)

Maximum Dose

(mg/day)

Duration of Action

Metabolism or Therapeutic Notes

Nonelderly Elderly

1st Generation

Acetohexamide 250, 500 250 125–250 500 1,500 Up to 16 hours

Metabolized in liver; metabolite potency equal to parent compound; renallyeliminated

Chlorpropamide 100, 250 250 100 250 500 Up to 72 hours

Metabolized in liver; also excreted unchanged renally

Tolazamide 100, 250, 500

100–250 100 250 1,000 Up to 24 hours

Metabolized in liver; metabolite less active than parent compound; renallyeliminated

Tolbutamide 250, 500 1,000–2,000 500–1,000

1,000 3,000 Up to 12 hours

Metabolized in liver to inactive metabolites that are renallyexcreted

70DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

SulfonylureasGeneric Name Dose

(mg)Recommended Starting Dosage

(mg/day)

Equivalent Therapeutic Dose (mg)

Maximum Dose

(mg/day)

Duration of Action


Nonelderly Elderly

2nd Generation

Glipizide 5, 10 5 2.5–5 5 40 Up to 20 hours

Metabolized in liver to inactive metabolites

Glipizide 2.5, 5, 10, 20

5 2.5–5 5 20 24 hours Slow-release form; do not cut tablet

Glyburide 1.25, 2.5, 5

5 1.25–2.5 5 20 Up to 24 hours

Metabolized in liver; elimination ½ renal, ½ feces

Glyburide, micronized

1.5, 3, 6 3 1.5–3 3 12 Up to 24 hours

Equal control, but better absorption from micronized preparation

Glimepiride 1, 2, 4 1–2 0.5–1 2 8 24 hours Metabolized in liver to inactive metabolites


Sulfonylureas Most common side effect: hypoglycemia

higher with chlorpropamide & glyburide; longer t½

high risk patients require lower doses

elderly

renal/hepatic disease

patients that skip meals

vigorous exercise

substantial weight loss

Weight gain also common

Less common adverse effects: rash, hemolytic anemia, GI upset, cholestasis

7272

Sulfonylureas Tolbutamide, chlorpropamide

hyponatremia may result from increased antidiuretichormone

disulfram-type reactions can result when alcohol is consumed

Titrate sulfonylureas doses every 1 to 2 weeks

Maximal effective dose ~60 to 75% stated max dose

At equipotent doses, all sulfonylureas equally effective at lowering blood glucose

7373

74

Sulfonylureas All sulfonylureas are metabolized in the liver

CYP2C9 involved in sulfonylurea metabolism

aMany drug interactions metabolism-basedbInducer


Drug Interactions with Sulfonylureas

Interaction Drugs

Displacement from protein binding sitesa

warfarin, salicylates, phenylbutazone, sulfonamides

Alters sulfonylurea hepatic metabolism (cytochrome P450)

chloramphenicol, monoamine oxidaseinhibitors, cimetidine, rifampinb

Altered renal excretion allopurinol, probenecid

Sulfonylureas Average HbA1c reduction: 1.5 to 2%

FBG reduction: 60 to 70 mg/dL

Most patients do not reach glycemic goal with monotherapy

1˚ failure: < 30 mg/dL drop in FBG

low C-peptide

high (> 250 mg/dL) FBG

2˚failure: good initial response, but insufficient to reach or maintain glycemic goal

5 to 7% per year failure rate 7575

Short-Acting Insulin Secretagogues

Generic Name

Dose (mg)

Recommended Starting Dosage

(mg/day)

Maximum Dose

(mg/day)

Duration of Action


Nonelderly Elderly

Nateglinide 60, 120 120 with meals

120 with meals

120 mg three times a day

Up to 4 hours

Metabolized by cytochrome P450 (CYP450), CYP2C9, and CYP3A4 to weakly active metabolites; renallyeliminated

Repaglinide 0.5, 1, 2 0.5–1 with meals

0.5–1 with meals

16 Up to 4 hours

Metabolized by CYP3A4 to inactive metabolites; excreted in bile

Stimulate insulin secretion from pancreatic β cells

require presence of glucose

Similar mechanism to sulfonylureas

faster onset, shorter duration


77

Short-Acting Insulin Secretagogues Most common adverse effect: hypoglycemia

less than with sulfonylureas

Weight gain may occur

repaglinide: 2 to 3 kg

nateglinide: < 1 kg

CYP3A4 inducers or inhibitors may interact with repaglinide

May use in patients with renal insufficiency

Use with caution in severe hepatic impairment

77

Short-Acting Insulin Secretagogues May be used as monotherapy or in combination with

metformin or TZDs in type 2 DM

Dose up to 30 min prior to each meal

dose can be skipped if a meal is skipped

meals low in carbohydrates may not need a dose

Average HbA1c reduction < 1%

Useful in reducing postprandial glucose excursions in patients close to glycemic goals

7878

Biguanide

Generic Name

Dose (mg) Recommended Starting Dosage (mg/day)

Maximum Dose

(mg/day)

Duration of Action


Nonelderly Elderly

Metformin 500, 850, 1,000

500 mg twice a day

Assess renal

function

2,550 Up to 24 hours

No metabolism; renally secreted and excreted

Metforminextended-release

500, 750, 1,000

500–1,000 mg with evening

meal

Assess renal

function

2,550 Up to 24 hours

Take with evening meal or may split dose; can consider trial if intolerant to immediate-release

Enhance hepatic & peripheral (muscle) tissue insulin sensitivity

increases uptake of glucose in tissues

No direct effect on β cells

Decrease hepatic glucose production


Biguanide Most common adverse effects: GI

abdominal discomfort, stomach upset, diarrhea

minimize with slow dose titration

may improve with time

administer with food to lessen adverse effects

switch to extended-release may improve tolerability

Weight loss can occur

anorexia

stomach fullness

8080

81

Biguanide Contraindications High risk patients for lactic acidosis

CHF, hypoxic states, shock, septicemia severe liver disease, alcohol use

Renal insufficiency

SCr ≥ 1.4 mg/dL in women

SCr ≥ 1.5 mg/dL in men

Intravenous dye procedures

risk of acute renal failure

withhold the day of procedure

may restart 2 to 3 days post-procedure

81

82

Biguanide Average HbA1c reduction: 1.5 to 2.0%

FBG reduction: 60 to 80 mg/dL

Reduce FBG levels when > 300 mg/dL

Decrease plasma triglycerides & LDL-C by ~8 to 15%

Increases HDL-C: 2%

Weight loss: 2 to 3 kg

Use in all type 2 DM patients if tolerated & not contraindicated

only oral antidiabetic agent proven to reduce mortality risk

UKPDS shows metformin is best suited for obese type 2 DM patients; reduces mortality

83

TZDs: Thiazolidinediones May be used in type 2 DM therapy

Enhance insulin sensitivity at muscle, liver, fat tissues

Decrease hepatic glucose production

Requires presence of insulin


Generic Name


Maximum Dose

(mg/day)

Duration of Action


Nonelderly Elderly

Pioglitazone 15, 30, 45 15 15 45 24 hours Metabolized by CYP2C8 and CYP3A4; two metabolites have longer half-lives than parent compound

Rosiglitazone 2, 4, 8 2–4 2 8 mg/day or 4 mg twice a

day

24 hours Metabolized by CYP2C8 and CYP2C9 to inactive metabolites that are renally excreted

TZD Adverse Effects May increase ALT

CI if ALT > 2.5 times upper limit of normal (ULN)

discontinue if ALT > 3 times ULN

troglitazone (1st approved TZD) removed from market in 2000 due to deaths from liver failure

Fluid retention

edema, dilutional anemia, pulmonary edema, HF

CI in NYHA Class III & IV

black box warning for chronic heart failure

84

TZD Adverse Effects Weight Gain

1.5 to 4 kg

fluid retention & fat accumulation

Increased fracture risk

upper & lower limbs of postmenopausal women

Ovulation

aovulatory patients can resume ovulation

pregnancy & contraception precautions required

pregnancy category C

85

TZDs Average HbA1c reduction ~1.5%

FBG reduction: 60 to 70 mg/dL at max doses

Maximal glycemic-lowering effects after 3 to 4 months

Triglycerides:

pioglitazone: 10 to 20% decrease

rosiglitazone: neutral effect

LDL:

pioglitazone: no significant increase

rosiglitazone: 5 to 15% increase

HDL: both increase 3 to 9 mg/dL8686

PROactive Prospective Pioglitazone Clinical Trial (PROactive)

Pioglitazone 45 mg added to standard therapy in patients with a macrovascular event or PVD

No significant difference in 1˚ end point: death, MI, stroke, ACS, leg or coronary revascularization, leg amputation

16% reduction (statistically significant) in 2˚ end points: all-cause mortality, nonfatal MI, stroke

209 admissions for HF with pioglitazone vs 153 in placebo group (p=0.007); no statistically significant increase in fatal HF

8787Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study prospective pioglitazone clinical trial in macrovascular events: a randomized controlled trial. Lancet. 2005; 366: 1279-1289.

DREAM Diabetes REduction Assessment with Ramipril and

Rosiglitazone Medication (DREAM)

1˚ endpoints: DM, death

Double-blind, placebo controlled trial

5,269 patients > 30 yrs old with IFG &/or IGT + no previous CVD (median follow up: 3 years)

randomized to rosiglitazone 8 mg daily or placebo

Rosiglitazone 8 mg daily

reduces incidence of type 2 DM

increases likelihood of regression to normoglycemia in adults with IFG &/or IGT

88

89

Clinical Controversy Rosiglitazone black box warning for myocardial

ischemia

issued due to a meta-analysis of 42 clinical studies comparing rosiglitazone to placebo

increased risk of MI events & death from CV causes

odds ratio for MI: 1.43 (95% CI, 1.03 to 1.98; p=0.03)

odds ratio for death: 1.64 (95% CI, 0.98 t0 2.74; p=0.06)

Other studies have not confirmed or excluded this risk

Currently, data on risk of myocardial ischemia are inconclusive

Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. 2007;356;2457-2471.

89

90

α-Glucosidase Inhibitors Competitively inhibit enzymes in the small intestine

delay sucrose & complex carbohydrate breakdown

Reduce postprandial hyperglycemia

Used in both type 1 & type 2 DM


Generic Name


Maximum Dose (mg/day)

Duration of Action


Nonelderly Elderly

Acarbose 25, 50, 100 25 mg one to three times a day

25 mg one to three times a day

25–100 mg three times a day

1–3 hours Eliminated in bile

Miglitol 25, 50, 100 25 mg one to three times a day

25 mg one to three times a day

25–100 mg three times a day

1–3 hours Eliminated renally

α-Glucosidase Inhibitors Adverse effect:

GI side effects most common

flatulence, bloating, abdominal discomfort, diarrhea

may elevate serum aminotransferase

Contraindications:

IBD

colonic ulceration

intestinal obstruction

cirrhosis

91

α-Glucosidase Inhibitors Efficacy

reduce postprandial glucose 40 to 50 mg/dL

FBG relatively unchanged (~10% reduction)

average HbA1c reduction: 0.3 to 1%

beneficial in patients close to target HbA1c with near-normal FBG but high postprandial levels

92

α-Glucosidase Inhibitor May be monotherapy or used with metformin,

sulfonylureas, insulin

Initiate with very low dose

25 mg with one meal a day

Increase gradually to maximum dose

50 mg TID patients ≤ 60 kg

100 mg TID patients > 60 kg

Take with 1st bite of a meal

must be present to inhibit enzyme activity

93

94

DPP-IV Inhibitors Inhibit DPP-IV which degrades GLP-1

prolongs GLP-1 t½

GLP-1 deficient in type 2 DM

Partially reduces elevated postprandial glucagon

Stimulates glucose-dependent insulin secretion


Generic Name Dose (mg) Recommended Starting Dosage (mg/day)

Maximum Dose

(mg/day)

Duration of Action


Nonelderly Elderly

Sitagliptin 25, 50, 100 100 mg daily 25 to 100 mg daily based on renal function

100 mg daily 24 hours 50 mg daily if: creatinineclearance > 30 to < 50 mL/minute25 mg if: creatinineclearance < 30 mL/min

95

DPP-IV Inhibitors May be used as monotherapy or in combination therapy

Average HbA1c reduction 0.7 to 1.0%

Mild hypoglycemia may occur

Postmarking reports of serious hypersensitivity reactions

anaphylaxis

angioedema

exfoliative skin conditions (Stevens-Johnson syndrome)

96

DCCT Diabetes Control and Complications Trial (DCCT)

Multicenter, randomized trial in type 1 DM patients

1,441 patients ages 13 to 39

2 groups

intensive therapy

conventional diabetes therapy

mean subject participation 6.5 yrs

Intensive therapy delays onset/slows progression of diabetic retinopathy, nephropathy, neuropathy

DCCT/EDIC study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643-2653.

DCCT/EDIC Diabetes Control and Complications Trial

(DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC)

Long-term follow-up (17 yrs) of DCCT subjects

incidence of cardiovascular (CV) disease in the intensive therapy vs. conventional group

Intensive diabetes therapy in type 1 DM patients

42% relative risk reduction for CV disease

57% relative risk reduction for nonfatal MI, stroke, death from CV disease

9797DCCT/EDIC study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643-2653.

98

UKPDS United Kingdom Prospective Diabetes Study (UKPDS)

Multicenter, randomized controlled trial 5102 newly diagnosed type 2 DM patients

followed ~10 yrs effect of glycemic control on diabetes complications

conventional (no drug therapy) vs. intensive (sulfonylurea or insulin) therapy

subgroup of obese patients received metformin

~50% of patients could not maintain glycemic control with monotherapy; required combination therapy

UKPDS Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.

UKPDS Intensive therapy:

12% reduction in diabetes-related endpoints

25% reduction in microvascular endpoints

minimal effect on macrovascular risk

no individual drug increased macrovascular disease risk

metformin reduces macrovascular risk in obese patients

tight BP control (mean 144/82 mm Hg) reduces both microvascular & macrovascular events

99UKPDS Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.

100100

β-cell preservation: future goal of treatment

UKPDS showed sulfonylureas, metformin & insulin do not stop progression of β-cell failure

TZDs, exenatide, DPP-IV inhibitors stop β-cell failure in animal models

improve short-term indirect β-cell function in humans

Long-term data is under review with incretin based therapies

Clinical Controversy

100

Clinical Controversy Action to Control CardiOvascular Risk in Diabetes Study

(ACCORD)

1˚ endpoint: nonfatal MI, stroke, death from CV causes

2˚ endpoint: death from any cause

10,251 patients ages 40 to 79 yrs (mean participation 3.5 years)

Type 2 DM + HbA1c ≥ 7.5 with high CV risk

2 groups: intensive therapy (target HbA1c < 6.0%); standard therapy (target HbA1c 7.0 to 7.9%)

Intensive therapy to target normal HbA1c levels increased mortality; did NOT reduce incidence of major CV events

101101Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59.

Action in Diabetes and Vascular Disease: Preterax ANdDiamicron Modified Release Controlled Evaluation (ADVANCE)

Combined 1˚ endpoint

macrovascular events: nonfatal MI, stroke, death from CV causes

microvascular events: nephropathy or retinopathy

Randomized to standard or intensive glucose control (HbA1c ≤ 6.5%)

102102The advance collaborative group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358;2560-2572.


ADVANCE

11,140 type 2 DM patients

age > 55 yrs

history of major macrovascular or microvascular disease or 1 other vascular disease risk factor

mean subject participation 5 years

Intensive glucose control reduced combined outcome of macrovasuclar & microvascular events

primarily by reduction in nephropathy

103The advance collaborative group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358;2560-2572.


Clinical Controversy Veterans Affairs Diabetes Trial (VADT)

Composite 1˚ endpoint of cardiovascular (CV) events MI

stroke

death from CV causes

CHF

surgical intervention for vascular disease

inoperable CAD

amputation for ischemic gangrene

104104Duckworth W, Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med. 2009;360:129-139.

Clinical Controversy VADT: open-label, randomized, dose comparison trial

1791 type 2 DM patients

2 groups

intensive: maximal doses

standard: 50% maximal doses

mean patient age: 60.4 yrs

mean subject participation: 5.6 yrs

Intensive glucose control: no significant effect on rates of major CV events, death, microvascular events

105Duckworth W, Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med. 2009;360:129-139.

106

Relationship between insulin & glucose over course of a day

Drug Combination Change in HbA1c (%)

Number of Studies

Number of Subjects

Sulfonylurea + metformin –2.2 8 458

Sulfonylurea + insulin –1.9 17 88

Meglitinide + thiazolidinedione –1.7 1 434

Metformin + insulin –1.7 8 138

Sulfonylurea + α-glucosidase inhibitor –1.6 3 177

Metformin + meglitinide –1.4 3 226

Insulin + α-glucosidase inhibitor –1.2 1 20

Insulin + thiazolidinedione –1.2 7 850

Sulfonylurea + thiazolidinedione –1.1 12 1,315

Metformin + exenatide –0.8 2 1,070

Metformin + vildagliptin –0.7 1 416

Metformin + thiazolidinedione –0.9 3 284

Metformin + α-glucosidase inhibitor –0.4 3 173

107

Add-Ona Dual Therapy: Average HbA1c Reduction


aReductions are averages and do not imply superiority or inferiority of a combination.


Multiple component insulin regimen: long acting insulin (^, one shot of glargine or two shots of detemir) for basal insulin coverage & 3 injections of a short-acting insulin analogue to provide glycemic coverage for each meal.

• y-axis shows amount of insulin effect; the x-axis shows time of day.

• B, breakfast; L, Lunch; S, supper; HS, bedtime.

• *Lispro, glulisine or insulin aspart can be used.

• Time of insulin injection shown with a vertical arrow.

Insulin Regimens

109

Insulin Regimens2 injections of long-acting insulin (^, NPH or detemir) & short acting insulin (solid red line) or regular insulin (green dashed line).

• B, breakfast; L, Lunch;

• S, supper; HS, bedtime.

• *Lispro, glulisine or insulin aspart can be used.


110

Insulin RegimensInsulin administration by infusion device with basal insulin & bolus injection at each meal. Basal insulin rate decreased during the evening & increased slightly prior to the patient awakening in the morning.

111

• B, breakfast; L, Lunch;

• S, supper; HS, bedtime.


112

Insulin Preprandial dose adjustment

dosing of insulin based on an adjusted scale given preprandially

intended to optimize the insulin regimen

Insulin correction factor

1800 should be used for rapid-acting insulin

Carbohydrate counting

General guidelines provide only estimates patients respond differently

112

1500 ÷ (total daily dose of insulin) = glucose lowering (mg/dL) effect of 1 unit of regular insulin

500 ÷ (total daily dose of insulin) = # of carbohydrate (grams) 1 unit of rapid or short-acting insulin will cover

Children & Adolescents Increasing incidence of type 2 DM in adolescents

Obesity, physical inactivity are causes

1˚treatment: lifestyle modifications

If lifestyle modifications fail:

metformin: labeled for use in children 10 to 16 yrs

sulfonylureas commonly used

TZDs not studied in children

exenatide has been used off-label

113113

Gestational DM Minimize wide fluctuations in blood glucose with

dietary changes

Initiate insulin if FBG > 105 mg/dL, 1 hour postprandial > 155 mg/dL, 2 hour postprandial > 130 mg/dL

Use of basal insulin other NPH still debated

Glyburide has been used for GDM, not a labeled use

further studies needed to establish safety

GDM patients at long-term risk for type 2 DM; assess periodically

114

Sick Days Acute self-limited illness

insulin sensitivity decreases; greater amount of insulin needed to control blood glucose

frequent SMBG, check urine ketones, use short-acting insulin to avoid diabetic ketoacidosis

must have glucose intake to cover insulin therapy & prevent hypoglycemia

115115

116

Diabetic Ketoacidosis Diabetic emergency

Precipitating Factors

insulin omission

illness, infection

initial DM presentation

Diagnostic laboratory values

hyperglycemia

anion gap acidosis

ketonemia, ketonuria

fluid deficits

Na+, K+ deficits116

117

Ketogenesis due to insulin deficiency leads to increased serum levels of ketones, ketonuria

Acetoacetate, β-hydroxybutyrate: ketone bodies produced by the liver; organic acids that cause metabolic acidosis

Respiration partially compensates; reduces PCO2: when pH < 7.20, deep, rapid respirations (Kussmaul breathing)

Acetone: minor product of ketogenesis; can smell fruity odor on breath of diabetic ketoacidosis patients

Diabetic Ketoacidosis Treatment: restore intravascular volume 1st

normal saline given acutely

switch fluids to D5W or D5W1/2NS when glucose ~250 mg/dL

hypotonic fluids to replace free H2O

K+ supplementation

potassium phosphate often used; no evidence of benefits

constant insulin infusion

118

Frequent glucose & K+ monitoring essential

K+ must be WNL before insulin is administered

Metabolic improvement: increased serum bicarbonate & pH

Glucose will fall before the anion gap closes

119

Diabetic Ketoacidosis

120

Hyperosmolar Hyperglycemia Diabetic emergency

Typically older type 2 DM patients

Fluid deficits & blood glucose concentrations generally greater than DKA

Precipitating Factors

infection/illness

prolonged hyperglycemia

dehydration

renal insufficiency

120

Hyperosmolar Hyperglycemia Lower blood glucose levels gradually

Treatment

Fluid replacement

hypotonic fluids (0.45% saline) should be used if serum sodium > 150 meq/L

low-dose insulin infusions (1 to 2 units/hour)

Avoid rapid correction of glucose levels

no greater than 75 to 100 mg/dL

may result in cerebral edema

121

Hospitalized DM Patients Patients on oral agents often receive insulin therapy for

adequate glycemic control during hospitalization

Insulin dosing

scheduled doses of long-acting insulin

additional short-acting insulin doses

Sliding scale alone is inappropriate

122


123123

No FDA-approved drugs to delay or prevent DM

ADA recommends metformin with lifestyle changes to for type 2 DM prophylaxis

many be better to treat diabetes early?

β-cell dysfunction seen in early IGT

STOP-NIDDM trial showed that acarbose delayed onset of type 2 DM in patients with impaired glucose tolerance

Prevention studies in progress with other medications

Chaisson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: The STOP-NIDDM randomised trial. Lancet 2002;359;2072-2077.

DM Complications Retinopathy

dilated eye examination annually

can reverse early retinopathy with improved glycemiccontrol

advanced retinopathy will not improve with glycemiccontrol; retinopathy can worsen with short-term glycemic improvements

124124

Diabetic Retinopathy

125

A hard caudate ring 1.5 disk diameters in

diameter is centered 1.0 disk diameter

superotemporal to the center of the

macula in this right eye. Part of the ring

is a plaque of hard exudate just above

the center of the macula. Within the ring,

many large microaneurysms can be

seen, some with visible walls (arrows).

They are slightly out of focus because

the retina here is thickened (edematous)

and the camera is focused on the

surrounding retina. With stereoscopic

viewing, retinal thickening was obvious

and could be seen to extend into the

center of the macula.

DM Complications Diabetic peripheral neuropathy

paresthesias, numbness, pain

feet more often than hands

improved glycemic control can alleviate symptoms

symptomatic therapy

topical capsaicin

NSAIDs, tramadol, opioids

low-dose tricyclic antidepressants

anticonvulsants: gabapentin, pregabalin

venlafaxine, duloxetine

126126

DM Complications

resting tachycardia

exercise intolerance

orthostatic hypotension

constipation

gastroparesis

impaired neurovascular function

erectile dysfunction

sudomotor dysfunction lack of sweating in

extremities

increased sweating in the trunk

hypoglycemic autonomic failure

127

Autonomic neuropathy

DM Complications Microalbuminuria, nephropathy

type 2 DM: urinary screening for albumin at diagnosis

type 1 DM: screen patients at puberty & 5 yrs after diagnosis

glucose & BP control

prevents nephropathy

slows nephropathy progression

1st line therapy: ACE inhibitors or ARBs

prevent renal disease progression in type 2 DM patients

128128

Diabetic Nephropathy

129Diabetic nephropathy, showing nodular glomerulosclerosis

Development of Renal Failure: Type 1 DM

130

DM Complications Peripheral vascular disease (PVD)

claudication

Treatment

smoking cessation

correction of dyslipidemia

antiplatelet therapy

revascularization in select patients

131131

DM Complications Nonhealing foot ulcers common in type 2 DM patients

Early treatment of foot lesions

local debridement

appropriate footwear

foot care

DM accounts for ~71,000 lower extremity amputations annually

132

Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008.

Parameter Goal Treatment (in order of preference)

LDL cholesterol < 100 mg/dL< 70 mg/dLa

Lifestyle; HMG-CoA reductase inhibitors; cholesterol absorption inhibitor; niacin or fenofibrate

HDL cholesterol Men> 40 mg/dL

Women> 50 mg/dL

Lifestyle; nicotinic acid; fibric acid derivatives

Triglycerides < 150 mg/dL Lifestyle; glycemic control; fibricacid derivatives; high-dose statins(in those with high LDL)

133

Hyperlipidemia in DM Patients

HDL, high-density lipoprotein

HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A

LDL, low-density lipoprotein.aCan be optimal goal in patients with preexisting cardiovascular disease.


DM Complications

134

Coronary Heart Disease (CHD)

CHD risk 2 to 4 times greater in diabetic vs. non-diabetic individuals

multiple-risk factor intervention reduces macrovascularevents

lipid management

HTN control

smoking cessation

antiplatelet therapy

NCEP ATP III guidelines: DM is a CHD risk equivalent

Clinical Controversy Japanese Primary Prevention of Atherosclerosis with

Aspirin for Diabetes (JPAD) Trial

1° endpoint: death from CHD or stroke; non-fatal MI or stroke; above ankle amputation

2,539 patients ages 30 to 85 yrs (mean participation 4.37 yrs)

type 2 DM + no history of atherosclerotic disease

2 groups: low-dose ASA (81 or 100 mg/day); non-ASA

Low-dose ASA as 1˚ prevention did not reduce risk of CV events

135Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008;300:2134–2141.

Clinical Controversy Prevention Of Progression of Arterial Disease And

Diabetes (PODADAD) trial

1° endpoint: atherosclerotic events

1,276 patients aged > 40 yrs (mean participation 4.37 yrs)

Type 1 0r 2 DM + ankle brachial pressure index ≤ 0.99 + no symptomatic CV disease

4 groups: 100 mg ASA + antioxidant; ASA + placebo; placebo + antioxidant; placebo + placebo

ASA or antioxidants as 1˚ prevention did NOT reduce CV events or mortality

136

Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840.

CARDS Collaborative AtoRvastatin Diabetes Study (CARDS)

Composite 1˚ endpoint: acute coronary heart disease, coronary revascularization, stroke

Multicenter, randomized placebo-controlled trial

2,838 type 2 DM patients

randomized to atorvastatin 10 mg/day or placebo

ages 40 to 75

without CV disease

without elevated LDL

mean subject participation 3.9 years

137137Colhoun HM, Betteridge DJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS): A multcentre, randomised placebo-controlled trial. Lancet 2004;364:685-696.

CARDS Atorvastatin 10 mg daily: reduces risk of 1st CV event in

type 2 DM patients without high LDL-cholesterol

relative risk reduction 37% [95% CI -52 to -17], p=0.001

No threshold in LDL–cholesterol levels for type 2 DM patients to receive statin therapy

138Colhoun HM, Betteridge DJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS): A multcentre, randomised placebo-controlled trial. Lancet 2004;364:685-696.

Heart Protection Study (HPS) 1˚ end point: mortality, non-fatal vascular events

Randomized, placebo-controlled trial

randomized to simvastatin 40 mg daily or placebo

5963 patients ages 40 to 80 years with DM & occlusive arterial disease (treatment for 5 years)

Cholesterol-lowering therapy beneficial for DM patients even without coronary disease or elevated cholesterol

24% reduction in the first occurrence of any vascular event affected individuals (95% CI 19-28; p<0.0001).

139Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-2016

Hypertension & DM ADA & the National Kidney Foundation recommend

target BP < 130/80 mmHg for DM patients

ACE inhibitors & ARBs: generally recommended as initial therapy

Many patients require multiple agents to obtain goals

diuretics, CCBs, β-blockers: 2nd & 3rd line agents

BP goals: more difficult to achieve than glycemic or lipid goals in most patients

140140

141141

Clinical Controversy ACE inhibitors & ARBs: typically initial choice for

HTN in DM

ARBs: less data to support cardiovascular reduction

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

diuretics had equivalent results to ACE inhibitors

Choice of monotherapy may not be important

on average: 2 to 3 antihypertensive medications needed to reach BP goals

141

Clinical Controversy Avoiding Cardiovascular Events through COMbination

Therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH)

Composite endpoint: death from CV causes, hospitalization for angina, nonfatal MI or stroke, coronary revascularization, resuscitation after cardiac arrest

Prospective, double-blind, industry sponsored trial randomized patients to benazepril + amodipdine or

benazepril + HCTZ 11,506 patients with HTN & high CV risk

Combination benazepril + amlodipine superior to benazepril + HCTZ for reducing CV events in high risk patients

142Jamerson KA, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension. N Engl J Med. 2009;359(23):2417-2428.

Recommended Monitoringblood pressure each visit

body weight/BMI each visit

hemoglobin A1c not at goal: every 10-12 weeksat goal: every 6 months

fasting lipid profile not at goal: each visit at goal: annually

foot exam each visit: physical exam; monofilament annually

urine albumin assessment annually

dilated ophthalmologic exam

annually; more frequently with identified abnormalities

pneumococcal vaccine At least 1 lifetime vaccination, vaccinate patients > age 64 if lastvaccination was > 5 years ago

influenza vaccine annually unless contraindicated

smoking cessation each visit

143

AcknowledgementsPrepared By: Aida Garza, Pharm.D.

Series Editor: April Casselman, Pharm.D.

Editor-in-Chief: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA

Chapter Authors: Curtis L. Triplitt, Pharm.D., CDE

Charles A. Reasner, II, MD

William L. Isley, MD

Section Editor: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA

Health & Medicine

Diabetes Mellitus Chapter 77