Diabetes Mellitus (CPR)

46 Diabetes Mellitus
JENNIFER D. SMITH
I. INTRODUCTION
A. Definition. The American Diabetes Association (ADA) defines diabetes mellitus as a group of
metabolic diseases characterized by inappropriate hyperglycemia resulting from defects in insulin
secretion, insulin action, or both. Symptoms of acute hyperglycemia include polyuria, polydipsia,
polyphagia, weight loss, blurred vision, fatigue, headache, and poor wound healing. Chronic hy-
perglycemia can lead to damage and potentially failure of various organs, including the eyes, heart,
kidneys, blood vessels, and nerves.
B. Classification. There are four clinical classes of diabetes: type 1, type 2, gestational, and other
specific types.
1. Type 1. Type 1 diabetes mellitus (T1DM) is typically characterized by an absolute insulin defi-
ciency attributed to an autoimmune destruction of the !-cells of the islets of Langerhans. Affected
individuals will have autoantibodies to glutamic acid decarboxylase, pancreatic islet ! cells, and/
or insulin. T1DM may be diagnosed at any age, but is most likely to be diagnosed prior to the age
of 30 years.
2. Type 2. Type 2 diabetes mellitus (T2DM) is the most common form of DM and is typically identi-
fied in individuals over the age of 30 years; however, it has become a more prominent diagnosis
in adolescents of certain ethnic origins (e.g., Hispanic, African American). Those diagnosed with
T2DM are typically overweight or obese, have a positive family history of diabetes, and/or exhibit
signs of insulin resistance (e.g., truncal obesity, high triglycerides, low high-density lipoprotein
cholesterol [HDL-C], acanthosis nigricans); autoantibodies found in T1DM are absent in T2DM.
3. Gestational diabetes mellitus. Gestational diabetes mellitus (GDM) is a condition in which
women first exhibit levels of elevated plasma glucose during pregnancy. Women previously diag-
nosed with diabetes prior to pregnancy are excluded from this classification. After pregnancy, the
diagnostic classification of GDM may be changed based on postpartum testing (see III.B.2.b).
4. Other specific types. Secondary diabetes occurs when the diagnosis of diabetes is a result of
other disorders (e.g., Cushing syndrome, acromegaly, cystic fibrosis, Down syndrome, pancre-
atic disorders) or treatments (e.g., glucocorticoids, antipsychotics). Monogenic DM (formerly
maturity-onset diabetes of the young) should be considered in children with an atypical presenta-
tion or response to therapy. Adults may present with Latent Autoimmune Diabetes of the Adult
(LADA), which is a slow destruction of the pancreatic !-cells similar to T2DM, but autoantibod-
ies are present as in T1DM.
5. Categories of increased risk for diabetes (prediabetes): Individuals who have elevated blood
glucose levels that do not meet diagnostic criteria for diabetes, but that are too high to be consid-
ered normal, are classified as having prediabetes. Prediabetes is a high-risk category for the future
development of T2DM.
C. Diabetes demographics and statistics
1. In the United States, an estimated 8.3% of the population has DM and 35% of adults (age 20 years
and older) have prediabetes.
2. Disparities exist in the diagnosis of diabetes across ethnic groups and minority populations, with
Native Americans and Alaska Natives having the highest rates of diagnosed diabetes (16.1%), fol-
lowed by blacks (12.6%) and Hispanics (11.8%).
3. T2DM accounts for more than 90% of the cases of diabetes.
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Diabetes Mellitus 931
II. PATHOPHYSIOLOGY OF THE DIABETIC STATE

A. Normal glucose regulation involves many factors including insulin, counterregulatory hormones,
incretin hormones, and amylin. Changes to any of these factors may result in an imbalance in
glucose levels.
1. Insulin regulates the metabolism of carbohydrate, protein, and fat as follows:
a. Promotes the cellular uptake of plasma glucose
b. Stimulates conversion of glucose into energy storage molecules (e.g., glycogen, fat) in the liver,
muscles, and adipose cells
c. Facilitates cellular uptake of amino acids and their incorporation into proteins
d. Inhibits production of glucose from liver, muscle glycogen, or amino acids
e. Decreases the breakdown of fatty acids to ketone bodies
2. Counterregulatory hormones in diabetes are hormones that work against insulin. Thus, where
insulin lowers blood glucose, counterregulatory hormones increase blood glucose. The counter-
regulatory hormones include:
a. Glucagon
b. Growth hormone
c. Catecholamines (epinephrine and norepinephrine)
d. Cortisol
3. Incretin hormones: Ingested glucose promotes a more rapid release of insulin from the pancreas
than when glucose is given by intravenous injection. This occurs because the incretin hormones,
gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by the intestines
in response to glucose ingestion, before the glucose is absorbed. Postprandial secretion of GLP-1 is
diminished in DM, whereas GIP secretion is normal or increased. Actions of GLP-1 include:
a. Increases glucose-dependent insulin secretion
b. Inhibits inappropriate glucagon secretion
c. Increases !-cell growth/replication
d. Slows gastric emptying
e. Suppresses appetite
4. Amylin is a hormone that is cosecreted with insulin from the pancreatic !-cells. Thus, in indi-
viduals with T1DM, little to no amylin is produced, whereas in T2DM, amylin is produced, but in
an insufficient quantity. Amylin lowers postprandial blood glucose levels by the following actions:
a. Prolongs gastric emptying time
b. Decreases postprandial glucagon secretion
c. Suppresses appetite
B. Development of diabetes
1. T1DM. Genetic predisposition, environmental factors, and autoimmunity have been proposed as
causes that lead to progressive !-cell dysfunction and eventually, overt diabetes mellitus. T1DM is
the result of immune-mediated destruction of the !-cells and is characterized by the abrupt onset
of clinical signs and symptoms.
a. Genetics. Human leukocyte antigens (HLAs) DQA and DQB appear to code for either dis-
ease susceptibility (DR3, DR4, HLA-DQA1*0301, and HLA-DQA1*0302) or resistance
(DRB1*04008-DQB1*0302, DRB1*0411-DQB1*0302). Greater than 90% of Caucasians diag-
nosed with T1DM have HLA-DR3 and/or HLA-DR4 present, but 95% of these individuals have
HLA-DQA1*0301 and HLA-DQA1*0302 present. However, in studies of identical twins, there
is a 50% discordance rate, suggesting that other factors such as the environment (e.g., infectious
agents, chemical agents, dietary agents) may be contributing factors to disease development. The
risk of developing T1DM is increased in the offspring of individuals diagnosed with diabetes.
b. Environment. Environmental triggers such as viral (e.g., rubella, Coxsackie B), chemical, or
dietary (e.g., cow’s milk) have been suspected in the development of T1DM.
c. Autoimmunity. An autoimmune component, possibly triggered by an environmental factor,
is involved in the development of T1DM. Anti-insulin or anti-!-cell antibodies are present in
the blood of most individuals at the time of diagnosis of T1DM. Antibodies to glutamic acid
decarboxylase (GAD) are found in the blood of approximately 70% of individuals diagnosed
with T1DM. Thus, the presence of these antibodies may serve as an immunologic predictor of
the future development of the disease.

932 Chapter 46 II. B
2. T2DM. Genetic factors, a !-cell defect, and peripheral site defects have been implicated.
a. Genetics. There is greater than a 90% concordance rate in identical twins if one has T2DM,
suggesting that the development of T2DM is predominately dependent on genetics. The risk
of offspring development of T2DM is at least 15%.
b. A primary !-cell dysfunction has been postulated in the development of T2DM because at
diagnosis, typically only about 50% of !-cells are functioning. The number of functioning
!-cells continues to decline with duration of the disease.
c. A peripheral site defect may also contribute to the expression of T2DM. Defects in postre-
ceptor binding or a decreased number of insulin receptors can lead to hyperglycemia.
3. Secondary diabetes may arise from other disorders (e.g., Cushing syndrome, acromegaly, cystic
fibrosis, Down syndrome, pancreatic disorders) or treatments (e.g., glucocorticoids, antipsychotics).
III. CLINICAL EVALUATION

A. Physical findings include the “polys” (e.g., polyuria, polydipsia, and polyphagia), weight loss, blurred
vision, fatigue, headache, frequent vaginal infections, and poor wound healing. Because hypergly-
cemia typically exists for extended periods prior to the diagnosis of T2DM, these persons may also
present with signs and symptoms of chronic complications from diabetes (see section X).
B. Diagnostic testing should be performed from venipuncture testing. Home blood glucose monitors
and point-of-care (POC) A1c monitors are not sufficiently accurate for diagnostic purposes. A1c
tests reflect the average blood glucose level over the preceding 2 to 3 months and correlate with an
estimated average glucose (eAG " 28.7 # A1C $ 46.7). A1c testing for diagnostic purposes should
not be done in individuals with abnormal red cell turnover (e.g., pregnancy, recent blood loss
or transfusion, some anemias). These individuals should only be diagnosed with glucose criteria.
Repeat testing, preferably with the same method, must be performed to confirm diagnosis, unless
there is unequivocal hyperglycemia (e.g., random blood glucose sample % 200 in a symptomatic
individual, hyperglycemia crisis). Fasting is defined as no caloric intake for at least 8 hrs.
1. Diabetes in nonpregnant adults and children
a. Fasting blood glucose ! 126 mg/dL
b. Random (casual) blood glucose and symptoms of hyperglycemia: ! 200 mg/dL
c. Oral glucose tolerance test (OGTT) using oral glucose load equivalent to 75 g anhydrous
glycerin dissolved in water: " 200 mg/dL
d. A1c ! 6.5%
2. Gestational diabetes mellitus (GDM) screening should occur between weeks 24 to 28 gestation
if not previously diagnosed with overt diabetes. A fasting 75-g oral glucose tolerance test (OGTT)
should be performed in the morning. Venipuncture should be measured at fasting and 1- and
2-hr post-oral glucose solution ingestion.
a. Diagnosis of GDM based on OGTT: Fasting & 92 mg/dL; 1 hr & 180 mg/dL; 2 hrs & 153 mg/dL.
b. If diagnosed with GDM, screening for persistent diabetes should occur between 6 to 12 weeks
postpartum and, if negative, at least every 3 years thereafter.
3. Prediabetes: relatively high risk for the future development of diabetes
a. Impaired fasting glucose (IFG): fasting blood glucose 100 to 125 mg/dL
b. Impaired glucose tolerance (IGT): OGTT results of 140 to 199 mg/dL
c. A1c 5.7 to 6.4%
4. Testing in asymptomatic individuals:
a. Adults who are overweight (BMI & 25 kg/m2) or who have one or more risk factors for diabe-
tes should be tested immediately and at least every 3 years thereafter if tests are negative. Risk
factors for diabetes include:
(1) Physical inactivity
(2) First degree relative with diabetes
(3) High-risk ethnicity (e.g., African American, Latino, Native American, Asian American,
Pacific Islander)
(4) Women who delivered a baby weighing & 9 lb or were diagnosed with GDM
(5) Hypertension (& 140/90 mm Hg or on therapy for hypertension)
(6) HDL cholesterol level ' 35 mg/dL and/or a triglyceride level % 250 mg/dL
(7) Women with polycystic ovarian syndrome (PCOS)

(8) Previous testing indicative of prediabetes

(9) Clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis
nigricans)
(10) History of CVD
b. Asymptomatic adults without risk factors should have screenings beginning at the age of
45 years.
c. Testing for T2DM in the asymptomatic pediatric population should occur at the age of
10 years or the onset of puberty (whichever comes first) in children who are overweight
(BMI % 85th percentile for age and sex; weight for height % 85th percentile; weight % 120%
for height) and have at least two risk factors (e.g., family history of diabetes in first or second
degree relative, race/ethnicity of African, Asian, or Native American or Latino, signs of insulin
resistance, or maternal history of GDM during child’s gestation). If negative, repeat testing
should occur every 3 years.
IV. GLYCEMIC TREATMENT GOALS. The two available techniques for monitoring glycemic
control are patient self-monitoring blood glucose (SMBG) and A1c. Important measurements for SMBG
include fasting plasma glucose (FPG) and 2-hr postprandial glucose (PPG). Guideline recommendations
for the use of these two techniques are provided by the American Diabetes Association (ADA) and the
American Association of Clinical Endocrinologists (AACE). The guideline recommendations differ
slightly, with those of AACE being more stringent (Table 46-1). All glucose targets should be individualized,
taking into account other disease states, age of person, duration of disease, and risk for hypoglycemia.
A. Outpatient glucose targets for nonpregnant adults:
1. ADA: A1c ' 7.0%; FPG 70 to 130 mg/dL; 1- to 2-hr PPG ' 180 mg/dL
2. AACE: A1c ( 6.5%; FPG ' 110 mg/dL; 2-hr PPG ' 140 mg/dL
B. Inpatient glucose targets for nonpregnant adults is specified by ADA and AACE as a glucose range of
140 to 180 mg/dL
C. Outpatient glucose targets for pregnant adults are the same for ADA and AACE guidelines. These
goals should be implemented, only if they can be achieved safely.
1. GDM: Preprandial ( 95 mg/dL; 1-hr PPG ( 140 mg/dL; 2-hr PPG ( 120 mg/dL
2. Preexisting T1DM or T2DM: A1c ( 6.0%; pre-meal, bedtime, and overnight values between 60
to 99 mg/dL; peak PPG of 100 to 129 mg/dL; A1c ' 6%
V. PHARMACOLOGIC TREATMENT OF DIABETES MELLITUS

A. Insulin and insulin analog (Table 46-2)
1. Types of insulin
a. Rapid-acting insulin. Lispro (Humalog), aspart (NovoLog), and glulisine (Apidra) insulins
b. Short-acting insulin. Regular insulin (Humulin regular, Novolin regular)
c. Intermediate-acting insulin. Isophane insulin suspension (neutral protamine Hagedorn;
NPH) insulin
d. Long-acting insulins. Glargine (Lantus) and detemir (Levemir) insulins.
Table 46-1 GUIDELINE RECOMMENDATIONS FOR OUTPATIENT GLYCEMIC

GOALS IN NONPREGNANT ADULTS1,2
American Diabetes American Association of Clinical

Association (ADA) Endocrinologists (AACE)
A1c goal ' 7.0% ( 6.5%

Fasting plasma glucose goal 70–130 mg/dL ' 110 mg/dL
Postprandial glucose goal ' 180 mg/dL ' 140 mg/dL
1
American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care 2012;35:s11–63.
2
AACE Diabetes Care Plan Guidelines. Endocrine Practice 2011;17(Suppl 2):1–53.

934 Chapter 46 V. A
Table 46-2 TYPES OF INSULIN—ONSET, PEAK, AND DURATION OF ACTIONa
Effective Variability in Absorption

Agent Onset (hr) Peak (hr) Duration (hr) and Duration
Rapid acting
Lispro (Humalog) ' 0.5 0.5–1.5 3–4 Minimal
Aspart (NovoLog) ' 0.5 0.7–1.0 3–5 Minimal
Glulisine (Apidra) ' 0.5 0.5–1.5 3–5 Minimal
Short-acting
Regular 0.5–1.0 2–4 5–8 Moderate
Intermediate-acting
NPH 2–4 6–10 10–16 High
Long-acting
Glargine (Lantus) 5 n/a 20–24 Minimal-to-moderate
Detemir (Levemir) 3–4 6–12 12–24 Minimal
a
Approximate time action in nonpregnant adult, with normal renal function.
n/a, not applicable; NPH, neutral protamine Hagedorn.
e. Premixed insulin products. Each mixture gives rapid- or short-acting insulin as a premeal bo-
lus plus an intermediate-acting insulin to control later hyperglycemia or the subsequent meal.
(1) 50/50 insulin: 50% protamine lispro insulin with 50% lispro insulin
(2) 70/30 insulin: 70% insulin aspart protamine with 30% aspart insulin or 70% NPH with
30% regular insulin
(3) 75/25 insulin: 75% protamine lispro insulin with 25% lispro insulin
f. Extemporaneous mixtures. Two insulins mixed in one syringe, before administration.
(1) Glargine and detemir should never be mixed in the same syringe with another insulin.
(2) When rapid-acting insulins (e.g., lispro, aspart, glulisine) are mixed with another insulin,
the preparation should be used immediately.
(3) Extemporaneous mixtures which include regular-acting and intermediate-acting insulin
are stable for 14 days refrigerated or 7 days at room temperature.
2. Chemical sources of commercial insulin available in the United States
a. Biosynthetic human, also called human insulin. Produced by recombinant DNA techniques
b. Insulin analog. Produced by chemical alteration of human insulin
3. Concentration of insulin products available in the United States
a. U-100: a concentration of 100 units/mL
b. U-500: a concentration of 500 units/mL
(1) Recommended for individuals with marked insulin resistance, requiring greater than
200 units of U-100 insulin daily.
(2) U-500, a highly concentrated insulin, is available by prescription only.
(3) Currently U-500 syringes are not available in the United States. Patients should be taught
to use the mL markings on a tuberculin or U-100 syringe to prevent dosing errors in units.
4. Indications. Insulin is required for glycemic management in individuals with T1DM and may be used
in combination with oral agents (e.g., metformin) or amylin agonists (e.g., pramlintide) as necessary.
Insulin may be an initial or adjunctive agent for individuals with T2DM and may be used in combina-
tion with oral agents, GLP-1 agonists (e.g., exenatide), or amylin agonists to achieve glycemic control.
5. Mechanism of action. Insulin exerts its effects in several ways, including the following:
(1) Stimulates hepatic glycogen synthesis
(2) Increased protein synthesis
(3) Facilitates triglyceride synthesis and storage by adipocytes; inhibits lipolysis
(4) Stimulates peripheral uptake of glucose
6. Initial dosage of insulin
a. T1DM, without concomitant infection or physiologic stress condition. Insulin should be
dosed based on weight and requires a calculation of the total daily dose (TDD). The total daily

dose for an adult with T1DM is estimated as 0.6 units/kg/day, which can then be applied to
determine an initial starting dose of insulin.
(1) 50/50 rule: 50% of the TDD is given as a basal (e.g., NPH, glargine, detemir) dose and the
remaining 50% is given as the bolus (e.g., regular, lispro, aspart, glulisine) dose, divided
between the meals. For example, if a person who weighs 120 lb is to start insulin, the esti-
mated TDD would be approximately 32 units. Half of the TDD (16 units) would be initi-
ated as the basal insulin and the remaining 16 units would be divided into an approximate
bolus dose as follows:
(a) Glargine or detemir as a basal with short- or rapid-acting insulin as bolus: 16 units
once daily of basal insulin; 5 units t.i.d. of bolus insulin with meals.
(b) NPH as a basal requires twice daily dosing in persons with T1DM. Also, when using
NPH, the total bolus dose should be decreased by 20% and given twice daily to pre-
vent hypoglycemia. Thus, the regimen for this example would be 8 units of NPH and
6 units of bolus, each given b.i.d.
(2) Premixed insulin should be initiated as two-third of the TDD in the morning and the
remaining one-third of the TDD in the evening, prior to meals. This means for the same
example used earlier with a TDD of 32 units, the insulin regimen would be 21 units in
the morning prior to breakfast and 11 units in the evening prior to the evening meal. It
should be noted that this type of dosing is not preferred for the individual with T1DM
because it cannot be easily adjusted for changes in diet, exercise, or health (e.g., sick days),
nor does it allow the titration of one insulin type to target the specific phase of insulin
release that is primarily contributing to the impaired glycemic control.
b. Type 2 DM
(1) Basal insulin alone may be initiated as 10 units once daily in the average-sized individual
or 0.1 to 0.2 units/kg/day in the overweight or obese individual. If administered in the
evenings, the dose of insulin should be titrated as necessary to achieve fasting blood glu-
cose levels in the target range. Bolus insulin can be added as needed based on pre- and
post-meal blood glucose monitoring.
(2) Premixed insulin should be initiated based on TDD of 0.2 units/kg/day, with two-thirds
of the TDD given in the morning prior to breakfast and one-third of the TDD given in
the evening prior to the last meal.
7. Insulin adjustment algorithms allow for the correction of an elevated blood glucose level or
dosing for carbohydrate intake. Though useful for optimizing glycemic control, adjustment algo-
rithms are not for everyone.
a. Adjustment based on blood glucose level: Several variations exist in the dosing of correction
insulin for elevated blood glucose. The rule of 1500 is typically used for dosing short-acting
(e.g., Regular) insulin, while the rule of 1800 is used for dosing rapid-acting insulin. However,
there are a myriad of algorithms used between 1500 and 2200. The higher the “rule” used, the
lower the risk of inducing hypoglycemia.
(1) The rule of 1800 is used to determine the correction factor (i.e., how many mg/dL the
blood glucose will decrease with the injection of 1 unit of insulin). The calculation is:
1800/TDD " correction factor (CF). For example, for the individual with a TDD of 32,
one unit of insulin should change the blood glucose level by approximately 56 mg/dL
(1800/32 " 56).
(2) The correction factor can then be used as a point-of-care calculation to determine how
much insulin to inject. The calculation is: [Current blood glucose—target blood glucose]/
CF. For the individual previously mentioned, if the blood glucose level is 230 mg/dL, to
achieve a target of 120 mg/dL with the above calculated CF of 56 mg/dL, the individual
would need to inject 2 units of rapid-acting insulin to bring the blood glucose back into
the target range. The target blood glucose is typically set by practice site protocol. The CF
should be rechecked at least once per year or when there is a significant change in weight,
as this is a weight-based calculation.
b. Adjustment based on carbohydrate intake uses the “rule of 500.” The “rule of 500” is as
follows: 500/TDD " (x) grams of carbohydrate. This equation estimates how many grams of
carbohydrates will be covered by 1 unit of insulin. Use of this rule requires the ability of the
individual with diabetes or the caretaker to count carbohydrates.

936 Chapter 46 V. A
8. Insulin adjustments for repeated, time-sequenced events of hypoglycemia or hyperglycemia: When

individuals experience repeated hypoglycemia or hyperglycemia at particular periods, several factors
should be taken into consideration (e.g., appropriateness of insulin dose(s), eating habits, changes in
exercise routine). Adjustments to insulin dosing should be made based on clinical evaluation of the
blood glucose levels and on the knowledge of insulin onset, peak, and duration of action (Table 46-2).
For example, if an individual who is taking 16 units of NPH insulin and 6 units of regular insulin
twice daily (6 a.m. and 6 p.m.) has in-target pre-lunch blood glucose levels, but is having hypoglycemia
pre-supper, a downward adjustment to the morning NPH dose would be most appropriate based on
its longer duration of action. Adjusting the morning dose of Regular insulin would be inappropriate
because the main effect of Regular insulin in this instance would be on the pre-lunch blood glucose
value. Changes in insulin doses may also be necessary for the following causes of hyperglycemia:
a. Dawn phenomenon produces fasting hyperglycemia due to the release of counterregulatory
hormones, which typically occurs during the early morning hours (2:00 a.m. to 4:00 a.m.).
Evening basal insulin doses should be increased or moved to bedtime dosing to correct for
hyperglycemia attributed to dawn phenomenon.
b. Somogyi effect is considered rebound hyperglycemia. This can occur at any time (day or
night) and is when the blood glucose goes too low and counterregulatory hormones are released
to increase the blood glucose. When the somogyi effect produces fasting hyperglycemia, the
evening basal doses of insulin should be decreased to prevent hypoglycemia.
9. Routes of insulin administration
a. Subcutaneous (SQ) injection is the method used most often for self-administration of insu-
lin. Vials of insulin with syringes have been the traditional method to deliver a SQ injection;
however, the insulin pens are rapidly becoming popular due to the convenience and portabil-
ity the devices offer (see section XII).
(1) Site selection: Insulin may be injected into the subcutaneous tissue of the abdomen,
buttocks, upper arm, and thigh (upper and outer only). The rate of absorption may dif-
fer depending on the anatomical site used. The abdomen is typically the fastest site for
insulin absorption, followed by the arm, buttocks, and thigh.
(2) Injection site rotation: Within an anatomical region, the injection site should be rotated
to avoid lipohypertrophy and fibrosis.
b. Continuous intravenous (insulin drip): The IV route is used to administer regular U-100
insulin, typically in a hospital setting, for the treatment of acute hyperglycemia, hyperglyce-
mic emergency (e.g., DKA or HHS), or during surgical procedures. The following applies to
transitioning from IV to SQ insulin:
(1) Short or rapid-acting insulin should be administered 1 to 2 hrs prior to IV insulin
discontinuation.
(2) Intermediate or long-acting insulin should be administered 2 to 3 hrs prior IV insulin
discontinuation.
c. Continuous subcutaneous infusion (insulin pump therapy) is a method to provide tighter
glycemic control by continuously infusing rapid-acting insulin into the body. Users must be
able to understand the complexity of the pump, check blood glucose levels, and determine
bolus insulin doses for dietary intake.
B. Insulin secretagogues (oral hypoglycemic agents)
1. Agents
a. Sulfonylureas generally target fasting blood glucose levels and are classified as first- or
second-generation agents.
(1) First-generation agents are typically not prescribed with the evolution of the second-
generation agents, which are associated with fewer adverse events. First-generation sulfo-
nylureas have been associated with thrombocytopenia, agranulocytosis, hemolytic anemia,
hyponatremia, SIADH, and disulfiram-like reactions. The three agents in this class include
tolbutamide (Orinase), tolazamide (Tolinase), and chlorpropamide (Diabinese).
(2) Second generation:
(a) Glyburide (DiaBeta, Glynase)
(b) Glipizide (Glucotrol)
(c) Glimepiride (Amaryl)

b. Meglitinides: Repaglinide (Prandin)

c. Phenylalanine derivatives: Nateglinide (Starlix)
2. Indication: The secretagogues are indicated for the management of T2DM only. The focus of
sulfonylureas is overall glycemic control, whereas the meglitinide and phenylalanine derivative
target postprandial control. Sulfonylureas have traditionally been seen as a first-line agent for the
management of T2DM; however, this class has lost some favor with the evolution of agents that
are multifactorial in the management of blood glucose.
3. Contraindications: Individuals with severe renal or hepatic dysfunction should avoid the use
of secretagogues. Caution should be used in the elderly due to the increased risk of falls with
hypoglycemic events. It should be noted that neither repaglinide nor nateglinide are effective in
patients who have failed sulfonylurea therapy.
4. Mechanisms of action: stimulates enhanced secretion of insulin from pancreatic !-cells, reduces
hepatic glucose output
5. Administration and dosage (Table 46-3)
6. Patient education and other concerns:
a. Hypoglycemia is an adverse effect of insulin secretagogues that warrants significant
counseling. Sulfonylureas are more likely to cause hypoglycemia, but repaglinide and
nateglinide are likely to induce hypoglycemia as well, if taken without food. Education
should include signs and symptoms of hypoglycemia and appropriate treatment (see IX.B
and IX.D).
b. Weight gain, secondary to increased insulin secretion, can occur.
C. Biguanides
1. Agents: The only available biguanide is metformin (Glucophage, Glucophage XR, Fortamet,
Glumetza, Riomet).
2. Indication: Metformin may be used for the glycemic management of T1DM or T2DM and is
recommended to be initiated at diagnosis of T2DM unless there is an existing contraindication.
Metformin primarily targets fasting blood glucose levels.
3. Contraindications
a. Renal disease: Metformin is contraindicated in renal disease due to the potential for lactic
acidosis. Metformin should be discontinued when the Scr is ! 1.4 mg/dL for females or
! 1.5 mg/dL for males. It should be understood that metformin does not cause renal dys-
function, but rather accumulation of the drug can contribute to toxicity (lactic acidosis) in the
individual with renal dysfunction.
b. Hepatic impairment or those with alcoholism or binge drinking
c. Heart failure: Metformin may be initiated or continued in those with stable heart failure; how-
ever, in unstable or acute heart failure, the risk of lactic acidosis can be increased secondary
to hypoperfusion.
d. Intravascular iodinated contrast media: Metformin should be withheld, if possible, at least
24 hrs prior to the procedure and may be reinitiated 48 hrs after, or when normal renal func-
tion returns. However, metformin can be withdrawn as few as 6 hrs prior to the procedure
with adequate hydration.
4. Mechanisms of action: The primary role of metformin is to inhibit hepatic glucose output, thus
exerting beneficial effects on fasting blood glucose levels. The secondary role of metformin is to
promote glucose uptake by fat and muscles, thereby improving insulin sensitivity. Thirdly, met-
formin has a minor role in decreasing intestinal absorption of glucose.
6. Patient education and other concerns
a. Up to 30% of individuals using metformin are affected by GI effects (e.g., abdominal
bloating, nausea, cramping, feeling of fullness, loss of appetite, or diarrhea). GI effects are
self-limiting over 7 to 14 days. Effects can be minimized by taking the medication with food,
starting with a low dose, and slow upward titration of dosage.
b. Minimal weight loss can be seen initially with this agent, but is not a continued effect.
c. Metformin use has been associated with a reduction in vitamin B12 levels. Monitoring of
vitamin B12 levels should be considered.
d. Miscellaneous effects include sweating and a metallic taste.

938 Chapter 46 V. C
Table 46-3 ORAL AND NONINSULIN INJECTABLE AGENTSa
Agent Initial Dose (Maximum Dose) Comments
#-Glucosidase Inhibitors
Adverse effects include diarrhea and abdominal
Acarbose (Precose) 25 mg t.i.d. with the first bite of each
stress, which is dose dependent and subsides
main meal (' 60 kg: 50 mg t.i.d.;
with continued use; adverse effects typically
% 60 kg: 100 mg t.i.d.)
limit the favorability of these agents
Miglitol (Glyset) 25 mg t.i.d. with first bite of each main
Glucose or lactose should be used to treat
meal (100 mg t.i.d.)
hypoglycemia that occurs within 2 hrs of
taking medication
Dose should be increased slowly as tolerated
Biguanide
Metformin (Glucophage, 500 mg once or twice daily with meals Adverse effects: transient nausea and
Glucophage XR, (Short-acting: 2550 mg/day; abdominal cramping (typically lasts up to
Glumetza, Fortamet, long-acting: 2000 mg/day) 2 weeks); lactic acidosis (rare, but fatal)
Riomet) Contraindicated in persons with renal or
hepatic disease, unstable heart failure, or
alcoholism
Thiazolidinediones (TZDs)
Pioglitazone (Actos) 15–30 mg once daily without regard to Adverse effects include weight gain and
meals (45 mg/day) peripheral edema
Rosiglitazone (Avandia) 4 mg once daily without regard to Contraindicated in hepatic disease and heart
meals (8 mg/day) failure (class III or IV)
Rosiglitazone has restricted access
Therapy may take 6–12 weeks for maximum
effectiveness
Sulfonylureas
Glipizide (Glucotrol, 5 mg once daily (Immediate release: Adverse effects: hypoglycemia, weight gain
Glucotrol XL) 40 mg/day; extended release: Micronized tablet (Glynase) formulation is
20 mg/day) NOT bioequivalent to regular glyburide
IR given 30 mins before a meal Contraindications: Glyburide is not
and % 15 mg/day is given in recommended if CrCl ' 50 mL/min;
divided doses however, glimepiride and glipizide may be
Glyburide (DiaBeta, DiaBeta: 2.5–5.0 mg/day with a meal used to a lower CrCl
Glynase PresTab) (20 mg/day)
Glynase 1.5–3.0 mg/day with a meal
(12 mg/day)
Glimepiride (Amaryl) 1–2 mg once daily with a meal
(8 mg/day)
Meglitinides
Repaglinide (Prandin) Not previously treated for DM or A1c Primary adverse effect: hypoglycemia
' 8%: 0.5 mg before each meal Targets postprandial blood glucose
Previously treated for DM or A1c values
% 8%: 1–2 mg before each meal
(16 mg/day)
Phenylalanine Derivatives
Nateglinide (Starlix) 120 mg t.i.d., up to 30 mins prior to Adverse effects: hypoglycemia; increased uric
each meal (180 mg/day) acid levels
If near goal A1c may initiate 60 mg t.i.d. Targets postprandial blood glucose values

Table 46-3 Continued.
DPP-IV Inhibitors
Sitagliptin (Januvia) 100 mg once daily regardless of a Adverse effects: upper respiratory tract
meal (100 mg/day) infection, nasopharyngitis, angioedema,
Saxagliptin (Onglyza) 2.5–5.0 mg once daily regardless of a urticaria
meal (5 mg/day) Sitagliptin and saxagliptin require
Linagliptin (Tradjenta) 5 mg once daily regardless of a meal dosage adjustments for CrCl ' 50 mL/min
(5 mg/day) All three may be used in mild-to-
moderate hepatic impairment
Avoid use in persons with pancreatitis
Drug–drug interactions: Saxagliptin levels may
be increased by strong CYP3A4 inhibitors
and the risk of edema is more than doubled
when combined with a TZD; saxagliptin dose
should be 2.5 mg when initiated with a TZD
or strong CYP3A4 inhibitor
Bile Acid Sequestrants
Colesevelam (Welchol) 1.875 g (3 tablets) b.i.d. or 3.75 g Adjunctive treatment only

(6 tablets) once daily Take other oral medications 1 hr before or
4 hrs after colesevelam
Avoid in persons with obstructive bowel
disease or triglyceride levels % 500 mg/dL
Dopamine Agonists
Bromocriptine (Cycloset) 0.8 mg once daily (4.8 mg/day) with a Adjunctive treatment only
meal within 2 hrs of wakening Adverse effects: gastrointestinal symptoms
Contraindications: use with caution in persons
with cardiovascular disease, peptic ulcer
disease, psychosis, or dementia
GLP-1 Agonists
Exenatide (Byetta) 5 mcg b.i.d. within 60 mins of a meal Available in pen devices for subcutaneous
(10 mcg b.i.d.) injection
Liraglutide (Victoza) 0.6 mg once daily regardless of a meal Adverse effects: Dose-related nausea and/or
(1.8 mg/day) vomiting that may decrease with continued
use, weight loss unrelated to GI symptoms,
possible pancreatitis, injection site reaction
Contraindications: Liraglutide is contraindicated
in persons with or a family history of
medullary thyroid cancer or in persons with
multiple endocrine neoplasia syndrome
type 2 (MEN2). Both liraglutide and
exenatide are contraindicated in persons
with pancreatitis or a history of pancreatitis,
T1DM, and gastroparesis
Slow titrations will minimize GI effects:
Liraglutide dose of 0.6 mg should be used
for 1 week prior to increasing to 1.2 mg/day;
exenatide 5 mcg b.i.d. should be used for
30 days prior to increasing to 10 mcg b.i.d.
Targets postprandial blood glucose
(Continued on next page)

940 Chapter 46 V. D
Table 46-3 Continued.
Amylin Agonists
Pramlintide (Symlin) T1DM: 15 mcg immediately prior to Adverse effects: nausea/vomiting, increased
meals (60 mcg t.i.d.) risk of severe hypoglycemia in persons with
T2DM: 60 mcg immediately prior to T1DM within 3 hrs of dosing
meals (120 mcg t.i.d.) Indicated for adjunctive therapy to basal and
bolus insulin: reduce prandial (bolus) insulin
by 50% when initiating pramlintide to avoid
hypoglycemia
Do not mix together with insulin or inject into
the same site as insulin
Drug–drug interactions: oral
medications needing rapid onset (e.g.,
analgesics) should be administered 1 hr
before or 2 hrs after pramlintide
Targets postprandial blood glucose
a
Consult package insert for detailed prescribing information. Dosage should be reduced if frequent hypoglycemia occurs without apparent
cause (e.g., medication error, changes in diet, exercise, timing of regimen).
BID, twice a day; CrCl, çcreatinine clearance; DM, diabetes mellitus; DPP, dipeptidyl peptidase; GI, gastrointestinal; GLP, glucagon-like peptide;
IR, immediate release; TID, three times a day; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
D. Thiazolidinediones (TZDs)
1. Agents
a. Pioglitazone (Actos)
b. Rosiglitazone (Avandia)
2. Indication: TZDs are indicated for glycemic control in T2DM and primarily affect the fasting
blood glucose levels.
a. TZDs should be used with caution in patients with hepatic dysfunction. Several linked cases
of liver toxicity are owed to troglitazone (Rezulin) which was removed from the market in
1999. Manufacturers of Avandia and Actos have taken caution, but have made great strides in
overcoming the stigma associated with the class. For instance, when the agents first became
available, LFTs had to be monitored every 2 months during the first year. In 2004, manufactur-
ers of the two available TZDs achieved FDA approval for LFTs to be monitored at baseline, at
6 months, and periodically thereafter.
b. Class III/IV heart failure: TZDs may cause fluid retention, which can exacerbate or lead to
heart failure. Patients should be observed for signs and/or symptoms of heart failure. In 2007,
FDA mandated manufacturers of TZDs to add CHF as a black box warning.
c. Anemia: TZDs may cause plasma volume expansion. This may result in a small decrease in
hemoglobin and hematocrit. Use cautiously in persons with anemia.
d. Fracture risk: TZDs have been associated with fractures, typically in the distal upper or lower
limbs of females.
e. Rosiglitazone has been associated with increased risk of cardiovascular events (e.g., myocar-
dial infarction, angina) and thus its use has been restricted by the Food and Drug Adminis-
tration (FDA). Rosiglitazone is available only from certain mail order pharmacies for certain
individuals under the Avandia-Rosiglitazone Medicines Access Program.
f. Pioglitazone is under an ongoing safety review for the potential increased risk of bladder
cancer. At this time, the FDA has not concluded an overall associated risk.
4. Mechanism of action: promote glucose uptake by fat and muscles and inhibit hepatic glucose
output by the stimulation of peroxisome-proliferator-activated receptor-gamma (PPAR-)).


a. TZDs as a class cause significant weight gain that is likely associated with fluid retention and
fat accumulation. Report unusual weight gain, shortness of breath, or swelling of the lower
extremities.
b. Benefits may not be seen prior to 2 to 4 weeks of use, with maximum effectiveness not seen
until 6 to 12 weeks of use.
E. #-Glucosidase inhibitors
1. Agents
a. Acarbose (Precose)
b. Miglitol (Glyset)
2. Indication: *-glucosidase inhibitors are for management of postprandial blood glucose
a. Inflammatory bowel disease, colonic ulceration, or obstructive bowel disorders
b. Acarbose is not recommended in patients with serum creatinine > 2.0 mg/dL and neither
agent is recommended in patients with creatinine clearance of ' 25 mL/min.
c. Acarbose is contraindicated in patients with hepatic impairment; dose-dependent elevation in
serum transaminases can be seen.
4. Mechanism of action: Competitive inhibition of alpha-glucosidases in the intestinal brush bor-
der, which leads to a slower absorption of complex carbohydrates.
a. *-glucosidase inhibitors cause increased gas formation in the colon, which can result in flatulence.
b. The dose should be taken with the first bite of the meal for effectiveness.
c. If hypoglycemia occurs within 2 hrs of dosing, patient should be treated with oral glucose
if the patient is conscious or intravenous glucose or glucagon if the patient is unconscious.
Lactose is also an acceptable alternative in the conscious patient.
d. GI side effects will lessen over time, but timing is variable for each patient.
F. Dipeptidyl peptidase-IV (DPP-IV) inhibitors
1. Agents
a. Sitagliptin (Januvia)
b. Saxagliptin (Onglyza)
c. Linagliptin (Tradjenta)
2. Indication: DPP-IV inhibitors are appropriate for use in individuals with T2DM with normal or
impaired hepatic and renal function.
a. Pancreatitis: use cautiously in an individual with a past medical history of pancreatitis and
discontinue use if an individual develops pancreatitis while on a DPP-IV inhibitor.
b. T1DM: DPP-IV inhibitors provide a glucose-dependent insulin secretion and thus are not
appropriate for individuals with T1DM.
4. Mechanisms of action: Prevents the inactivation of incretin hormones (e.g., GLP-1) by the en-
zyme DPP-IV. GLP-1 works to stimulate insulin secretion and decrease glucagon secretion from
the pancreas during hyperglycemia; thus inhibiting the breakdown of GLP-1 would allow for
increased insulin secretion and decreased hepatic glucose production.
a. Notify prescriber if develop signs/symptoms of pancreatitis (e.g., persistent abdominal pain,
nausea, or vomiting).
b. Hypersensitivity reactions may include angioedema, severe skin rash, or difficulty breathing.
G. Bile acid sequestrant
1. Agent: Colesevelam (Welchol)
2. Indication: adjunctive therapy for the management of T2DM
a. Persons with a history of bowel obstruction, hypertriglyceridemia-induced pancreatitis, or
serum triglyceride concentration % 500 mg/dL.
b. Persons with gastroparesis or other severe GI motility disorders due to constipating effects

942 Chapter 46 V. G
4. Mechanism of action for improved glycemic control is unknown.

a. Oral medications should be taken 1 hr before or 4 hrs after colesevelam.
b. Constipation is the most common adverse effect.
H. Dopamine agonist
1. Agent: Bromocriptine (Cycloset)
2. Indication: adjunctive therapy for the management of T2DM
3. Contraindications: Use with caution in persons with cardiovascular disease (e.g., myocardial in-
farction, arrhythmias), dementia, psychosis, or peptic ulcer disease.
4. Mechanism of action for improvement in glycemic control is unknown; however, it is postulated that
bromocriptine may affect circadian rhythms, which may play a role in obesity and insulin resistance.
a. May cause dizziness and fatigue. Use caution when performing tasks that require mental alertness.
b. May cause gastrointestinal discomfort, nausea, or vomiting. Take with food to lessen gastro-
intestinal discomfort.
c. Take within 2 hrs after waking in the morning. Dose will be increased weekly until the maxi-
mum tolerated dose is achieved.
I. Available oral combination products
1. Metformin/glyburide (Glucovance)
2. Metformin/glipizide (Metaglip)
3. Metformin/rosiglitazone (Avandamet): restricted access medication
4. Metformin/pioglitazone (Actoplus Met, Actoplus Met XR)
5. Metformin/repaglinide (PrandiMet)
6. Metformin/saxagliptin (Kombiglyze)
7. Metformin/sitagliptin (Janumet, Janumet XR)
8. Rosiglitazone/glimepiride (Avandaryl): restricted access medication
9. Pioglitazone/glimepiride (Duetact)
J. Incretin mimetics (GLP-1 agonists)
1. Agents
a. Exenatide (Byetta)
b. Liraglutide (Victoza)
2. Indication: management of T2DM
a. Individuals with severe GI motility disease (e.g., gastroparesis)
b. Pancreatitis or a history of pancreatitis
c. Severe renal impairment or hepatic impairment
d. Liraglutide is contraindicated in individuals with a history or family history of medullary
thyroid carcinoma (MTC) and individuals with multiple endocrine neoplasia syndrome type 2
(MEN2). It may be used in individuals with other thyroid disorders, including hypothyroidism
or hyperthyroidism.
4. Mechanisms of action. Increases glucose dependent insulin secretion, decreases hepatic glucose
output, increases !-cell growth and replication, slows gastric emptying, and enhances satiety.
a. Exenatide should be administered within 60 mins of a meal twice daily. Liraglutide may be
dosed independent of meals once daily.
b. Administration sites include the upper arm, thigh, or abdomen.
c. Nausea and vomiting may occur with initiation and dose changes, but is typically a transient
effect. Weight loss is a sustained effect unrelated to gastrointestinal effects.
d. Report unusual lump or swelling of the neck, difficulty swallowing, or unusual hoarseness
with the use of liraglutide.
K. Amylin receptor agonist
1. Agent: Pramlintide (Symlin)
2. Indication: enhanced postprandial control in individuals with T1DM or T2DM

3. Contraindication: Use should be avoided in individuals with gastric motility disorders, such as
gastroparesis
4. Mechanisms of action. Slows gastric emptying; decreases postprandial glucagon secretion; sup-
presses appetite
a. When concomitantly given with insulin, may produce severe hypoglycemia within 3 hrs of
administration.
b. Pre- and post-blood glucose monitoring should be used to determine efficacy of agent.
c. Administration is into abdomen or thigh; injection into upper arm should be avoided due to
variable absorption.
d. Oral medications needing rapid onset of action (e.g., antibiotics, analgesics) should be admin-
istered 1 hr before, or 2 hrs after pramlintide.
e. Do not mix in same syringe as insulin. Inject at least 2 inches away from insulin injection.
L. Emerging treatment options
1. Once weekly exenatide (Bydureon)*: Dosed once weekly as a 2 mg subcutaneous injection, this
agent targets over-all blood glucose control rather than postprandial as seen with other GLP-1
agonists; because it takes 6 weeks for this agent to hit steady state, there is no dose titration neces-
sary and less pronounced gastrointestinal effects. Onset of action is approximately 2 weeks.
2. Sodium glucose transporter 2 (SGLT2) inhibitors: SGLT2 is a transporter in the kidneys that
is responsible for approximately 90% of renal glucose reabsorption. The SGLT2 inhibitors are
proposed to inhibit this transporter, thus increasing the urinary excretion of glucose and lower-
ing blood glucose levels. These agents are unique in that they provide an insulin-independent
mechanism of action with near absence of hypoglycemia. Agents currently in clinical trials in-
clude dapagliflozin, sergliflozin, and remogliflozin.
VI. GLYCEMIC MANAGEMENT OF T2DM

A. Initiation of therapy. Unless contraindications exist, metformin is the preferred initial agent for the
management of T2DM. However, therapy should be individualized, taking into account the signifi-
cance of the hyperglycemia and the desired target of therapy.
1. Treatment based on current A1c level:
a. 6.5% to 7.5%: Metformin is the preferred initial agent, but a DPP-IV inhibitor, GLP-1 agonist,
or *-glucosidase inhibitor may be considered when the postprandial blood glucose is of most
concern. A TZD may also be initial therapy when metabolic syndrome and/or nonalcoholic
fatty liver disease (NAFLD) is present. Monotherapy should be tried for 2 to 3 months with
the initiating agent prior to adding other agents to the regimen.
b. 7.6% to 9.0%: Dual therapy should be initiated with metformin providing the backbone of
therapy, unless contraindicated. A GLP-1, DPP-IV inhibitor, TZD, sulfonylurea, or meglitinide
may be used in combination with the metformin. The chosen therapy should be continued for
2 to 3 months before consideration of an additional agent for glycemic control.
c. " 9.0%
(1) Symptomatic: Insulin with or without additional oral agents
(2) Asymptomatic: Dual or triple oral therapy with metformin as the backbone.
2. Targeted blood glucose control
a. Fasting blood glucose target: consider metformin, sulfonylurea, TZD, or long-acting basal
insulin
b. Postprandial blood glucose target: consider GLP-1 agonist, meglitinide, rapid-acting insu-
lin, or *-glucosidase inhibitor
B. Management. Maintaining glycemic control should also be individualized. Consideration should be
given to initiating insulin if more than three oral agents are needed to maintain glycemic control or
if the A1c remains % 8.5% with dual oral therapy.
*In January 2012, Bydureon (long-acting exenatide) was FDA-approved for once weekly injection as adjunct therapy in the management of
type 2 diabetes. Mixing of the agent is required immediately prior to injection.

944 Chapter 46 VII
VII. PHARMACOLOGIC THERAPY OF PREDIABETES. Therapy with data to delay

or prevent the disease progression include metformin, pioglitazone, orlistat, and alpha-glucosidase
inhibitors (e.g., miglitol, acarbose).
VIII. HYPERGLYCEMIC EMERGENCIES. The two most common hyperglycemic emergencies

are diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). DKA and HHS differ
in the presence of ketoacidosis and the degree of hyperglycemia (Table 46-4).
A. DKA, which is caused by profound insulin deficiency, typically occurs in persons with T1DM, but
can also occur in those with T2DM. It is characterized by hyperglycemia, ketosis, dehydration, and
electrolyte imbalance.
1. Pathophysiology
a. Insulin deficiency leads to the following actions:
(1) impairs glucose uptake in the peripheral tissues, resulting in hyperglycemia
(2) impairs protein synthesis and promotes breakdown of protein, thus leading to a loss of
lean body mass
(3) increases hydrolysis of triglycerides, which leads to increased hepatic glucose production
(further hyperglycemia) and formation of ketone bodies
b. Hyperglycemia causes osmotic diuresis, which leads to hypotonic fluid losses, dehydration,
and electrolyte depletion.
2. Precipitating factors: illness or infection, inadequate dosing of insulin or discontinuation of
insulin
3. Signs and symptoms often include those typical of hyperglycemia (e.g., polyuria, polydipsia,
weight loss, blurred vision), Kussmaul respirations (deep, rapid breathing), dehydration, and
mental status changes. Persons may appear lethargic, have a fruity odor to the breath, or have
gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain).
4. Laboratory findings typically include plasma glucose level % 250 mg/dL, but ' 600 mg/dL; posi-
tive urine and serum ketones; arterial pH ' 7.3; sodium bicarbonate ' 15 mEq/L
5. Treatment is focused on correction of dehydration, hyperglycemia, and electrolyte imbalance.
Treatment may include any of the following as necessary: IV fluids, insulin, potassium, and/or
sodium bicarbonate.
B. HHS predominantly affects elderly individuals and is an extreme manifestation of impaired glucose
regulation. HHS is associated with a higher mortality than DKA, likely due to severe metabolic
changes, delay in diagnosis, or other medical complications that can affect the elderly individual.
1. Pathophysiology: The pathogenesis of HHS is not as clear as DKA. However, HHS does differ
from DKA in that insulin deficiency is not as profound, thus increased lipolysis does not occur.
Table 46-4 RECOGNITION OF DKA AND HHS3
DKA HHS
Onset Sudden Gradual

Affected individuals T1DM (occasionally T2DM) Elderly
Plasma glucose Between 250 mg/dL and 600 mg/dL % 600 mg/dL
Gastrointestinal symptoms (e.g., nausea, vomiting, Present Negative
abdominal pain)
Serum or urine ketones (nitroprusside reaction) Positive Minimal to none
Kussmaul respirations Positive Negative
Arterial pH ' 7.3 % 7.3
Serum osmolality 2[(sodium + glucose)/18] Variable % 320 mOsm/kg
Sodium bicarbonate ' 15 mEq % 15 mEq
DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
3
American Diabetes Association. Position statement: Hyperglycemic crises in patients with diabetes. Diabetes Care 2003;26:s109–117.

Individuals with HHS do have osmotic diuresis that produces dehydration, electrolyte depletion,
and hypotonic fluid loss to a greater extent than seen in DKA.
2. Precipitating factors: illness or infections, hypertonic feedings, excessive fluid loss secondary to
hyperglycemia, severe burns, severe diarrhea, dialysis, or the use of diuretics
3. Signs and symptoms may include hyperglycemic symptoms (e.g., polyuria, polydipsia, polypha-
gia, blurred vision, decreased wound healing), decreased mentation (e.g., lethargy and mild con-
fusion), or focal neurological signs that mimic a cerebrovascular accident.
4. Laboratory findings typically include plasma glucose levels % 600 mg/dL, normal sodium
bicarbonate level, minimal to no ketones, normal arterial pH, and high serum osmolality
(measure of dehydration).
5. Treatment goals are similar to DKA; however, in HHS, caution should be used with aggressive
fluid replacement to avoid fluid overload in elderly individuals.
IX. HYPOGLYCEMIA. Hypoglycemia is the limiting factor for providing aggressive insulin therapy
in individuals with T1DM or T2DM.
A. Definition. Hypoglycemia is difficult to define, but typically is represented by plasma glucose levels
' 70 mg/dL. However, symptoms are the driving determinant rather than an absolute glycemic value
since the threshold for the onset of symptoms varies among individuals.
B. Symptoms of mild hypoglycemia include sweating, shaking, vision changes, immediate hunger,
confusion, and lack of coordination. Severe hypoglycemia occurs when an individual is unable to self-
treat due to mental confusion, lethargy, or unconsciousness. Some individuals may have neuroglyco-
penia and present with symptoms of crying, argumentativeness, inappropriate giddiness, or euphoria.
C. Causes can include advanced age, poor nutrition, renal disease, excess of glucose-lowering agents
(insulin or insulin secretagogues), or strenuous activity.
D. Treatment
1. Mild hypoglycemia: Individuals should check their blood glucose level prior to treating, if possible.
If the blood glucose level is low, the person should eat or drink 10 to 15 g of a fast-acting glucose
source (e.g., 4 oz of fruit juice or regular soda, 3 pieces of peppermint candy) to raise the plasma
glucose level 30 to 45 mg/dL. If plasma glucose levels are ' 50 mg/dL, treatment with 20 to 30 g of
carbohydrate may be necessary. The blood glucose level should be rechecked 15 to 20 mins after
treatment. If blood glucose levels are low, then hypoglycemia treatment can be repeated.
2. Severe hypoglycemia: Individuals able to swallow may be treated with glucose gel, syrup, or jelly
placed inside the individual’s check. If this is not possible, glucagon, which stimulates hepatic
glucose production, may be given by SQ or IM injection. Nausea and vomiting are primary
adverse effects of a glucagon injection, so the treated person may not immediately feel like con-
suming further carbohydrates. However, the glycemic response to glucagon is transient (approxi-
mately 1.5 hrs), so a small snack should be eaten when the individual is able.
E. Other types of hypoglycemia
1. Pseudohypoglycemia occurs when the individual perceives hypoglycemic symptoms, but the
blood glucose level may be normal, or slightly above normal. Some literature states that there is no
need to treat pseudohypoglycemia; however, providing 5 to 10 g of a rapid-acting glucose source
can diminish the symptoms without causing significant elevations in blood glucose.
2. Hypoglycemia unawareness occurs when hormonal counterregulation and autonomic symp-
toms disappear. However, individuals do typically have select symptoms, such as those associated
with neuroglycopenia, but they may be recognized too late to allow for timely treatment.
X. CHRONIC COMPLICATIONS
A. Macrovascular complications include three major types: coronary artery, cerebral vascular, and
peripheral vascular disease. These events occur earlier and at a higher rate in those with diabetes
than those who do not have diabetes. Attention to multiple risk factors (e.g., lipids, blood pressure,
smoking cessation, and antiplatelet therapy) for prevention of these complications is paramount in
the diabetes care plan.
1. Dyslipidemia: The primary focus of lipid management is to lower LDL to $ 100 mg/dL
in those without overt CVD and ' 70 mg/dL in those individuals with overt CVD (optional

946 Chapter 46 X. A
goal). However, the triglyceride value may be the primary target when it exceeds 400 mg/dL.
When controlled, the focus should return to lowering the LDL levels. Statins are the drug of
choice in lowering LDL levels and should be initiated in any patient with overt CVD and any
patient over the age of 40 without overt CVD but with other CVD risk factors, regardless of
baseline LDL. Goals for HDL and triglycerides levels are " 40 mg/dL and $ 150 mg/dL,
respectively. Of note, correcting poor glycemic control will have positive impact on the
triglyceride levels.
2. Hypertension: Development of hypertension in persons with T1DM is often the result of ne-
phropathy, whereas in T2DM, it is part of the conglomeration of cardiovascular risk factors.
The goal blood pressure should be ' 130/80 mm Hg, but this may require more than 2 agents
at maximum doses in the individual with diabetes. Initial therapy should be with either an
ACE-I or ARB; a thiazide diuretic can be added, if necessary, to meet the blood pressure goal.
Lifestyle modifications should include reduction in sodium intake (' 1500 mg/day), weight
loss (if appropriate), increased physical activity, and increased consumption of fresh fruits and
vegetables.
3. Smoking cessation should be recommended at every visit for individuals who smoke because
nicotine contributes significantly to the development of both macrovascular and microvascular
complications of diabetes.
4. Antiplatelet therapy: Aspirin therapy has cardiovascular morbidity and mortality data when
used as secondary prevention, but the benefits of aspirin for primary prevention is more contro-
versial.
a. Aspirin (75 to 162 mg/day) should be considered for primary prevention in those with T1DM
or T2DM who are at increased cardiovascular risk (e.g., men % age 50 or women % age 60
with another CVD risk factor).
b. Aspirin is currently not recommended for primary prevention in individuals with diabetes
who are at low CVD risk because risks outweigh benefits.
c. Aspirin should be used as secondary prevention in any individual with diabetes and a history
of CVD. If aspirin cannot be tolerated, clopidogrel 75 mg/day should be used.
B. Eye disease, considered a microvascular complication, is 25 times more common in the individual
with diabetes. In fact, diabetes is the leading cause of new blindness in the United States. Several
significant diabetic eye complications can occur (e.g., vitreal hemorrhage, retinal detachment), but
diabetic retinopathy is the most common.
1. Cause: Diabetic retinopathy occurs when damage occurs to the retinal blood vessels, resulting in
leakage of blood components through the vessel walls.
2. Classification: Retinopathy may be classified as proliferative diabetic retinopathy (PDR) or
nonproliferative diabetic retinopathy (NPDR).
a. PDR occurs in response to the lack of oxygen following capillary closure. New vessels are
formed along the surface of the retina, but these new vessels are weak and prone to rupture,
leading to vitreous hemorrhage and/or macular edema. Visual alteration can range from mild
blurring of vision to severe visual obstruction.
b. NPDR occurs prior to growth of new blood vessels along the retina and may remain asymp-
tomatic for years. NPDR can range from mild to severe and is typically progressive.
3. Prevention measures include optimizing control of blood glucose and blood pressure, achieving
lipid goals, and avoidance of nicotine-containing products. Routine dilated eye exams should oc-
cur within 5 years of diagnosis of T1DM and at diagnosis of T2DM and annually thereafter. Some
individuals may be cleared to have eye exams performed at 2-year intervals, but the standard
recommendation is an annual exam.
4. Treatment: NPDR management is by observation and modifying risk factors. PDR can be treated
with panretinal photocoagulation to reduce severe vision loss.
C. Diabetic nephropathy. Approximately 20% to 40% of individuals with diabetes will develop dia-
betic nephropathy, which is the leading cause of end-stage renal disease (ESRD). Markers of kidney
damage (e.g., serum creatinine, urine microalbumin levels) are used to detect early stages of kidney
disease.
1. Assessment: Persistent microalbuminuria is the earliest stage of kidney disease in individuals
with T1DM and a marker for the future development in those with T2DM. Serum creatinine is

used to estimate the glomerular filtration rate (GFR) and stage the level of chronic kidney dis-
ease (CKD).
a. Albumin-to-creatinine ratio in random spot collection can be used to screen for microalbu-
minuria or macroalbuminuria.
(1) Classification
(a) Normal: ' 30 ,g/mg creatinine
(b) Microalbuminuria: 30 to 299 ,g/mg creatinine
(c) Macroalbuminuria : " 300 ,g/mg creatinine
(2) Interpreting results: At least two positive screenings should occur within a 3- to 6-month
period to classify an individual as having microalbuminuria or macroalbuminuria, due
to the variability in urinary albumin excretion. Levels may be affected by exercise within
24 hrs, infection, fever, heart failure, or significant hyperglycemia or hypertension.
b. Serum creatinine should be measured at least annually, regardless of the albumin-to-creat-
inine ratio. Scr levels can then be used to determine an estimated GFR for staging chronic
kidney disease, which ranges from Stage 1 (kidney damage with GFR & 90 mL/min) to Stage 5
(kidney failure with GFR ' 15 mL/min or dialysis).
2. Prevention: attaining and maintaining glycemic and blood pressure control, dietary protein re-
striction, and the use of ACEI or ARB
3. Treatment for microalbuminuria or macroalbuminuria should be with an ACE-I or ARB to slow
the progression of renal disease. ARBs have data to support their use in individuals with T2DM
and macroalbuminuria.
D. Diabetic neuropathies include distal symmetric polyneuropathy (DPN) and autonomic neuropathy.
1. Peripheral neuropathy, also known as DPN, is a major pathophysiologic risk factor for foot ul-
ceration and amputation.
a. Presentation: DPN occurs at the most distal portions of the lower extremities in a “stocking
and glove” pattern. Protective sensation is first diminished in the toes and feet, then in the
fingers and hands. Affected individuals may complain of burning, numbness, or tingling in
the lower extremities.
b. Screening should occur at least annually with several simple clinical tests, including the vi-
bration perception (using a 128-Hz tuning fork) and 10-g monofilament pressure sensation.
c. Treatment is for symptomatic relief and may include antidepressants, anticonvulsants, or
opioids.
2. Autonomic neuropathy involves multiple systems throughout the body, including the cardiovas-
cular, gastrointestinal, and genitourinary systems.
a. Presentation: Clinical manifestations include resting tachycardia, exercise intolerance, or-
thostatic hypotension, constipation, gastroparesis, erectile dysfunction, and hypoglycemia
unawareness.
b. Treatment: Improve glycemic control; symptoms associated with the gastrointestinal and gen-
itourinary tracts may be improved with pharmacologic agents, but progression of the disease
will not be affected.
XI. PATIENT EDUCATION AND SELF-CARE. Education and development of self-

management goals should be provided for individuals diagnosed with diabetes and prediabetes. Self-
care for diabetes typically involves significant lifestyle changes, including dietary changes and activity
implementation. Lifestyle changes can often be difficult and therefore require positive reinforcement and
involvement of the person with diabetes in the decision-making process.
A. Medical Nutrition Therapy (MNT) is nutrition care that provides assessment, education, goal set-
ting, and evaluation of outcomes in an attempt to attain and maintain optimal metabolic control
(e.g., glucose, lipid, and blood pressure goals). Exchanges, based on the amount of carbohydrates in
different food groups, were previously recommended for regulating blood glucose levels. However,
this strategy has been replaced by carbohydrate counting and the plate method.
1. Carbohydrate counting: Consistency in carbohydrate intake at meals and snacks is essential for
achieving glycemic control, particularly for the postprandial blood glucose levels. Foods that con-
tain a significant amount of carbohydrates (e.g., breads, milk, fruit, rice, beans, corn, and potatoes)

948 Chapter 46 XI. A
1 fruit
serving ¼ plate
of meat Sugar-free
beverage
½ plate of
nonstarchy
vegetables
¼ plate
of starch
Figure 46-1. The plate method.
should not be eliminated from the meal plan, but incorporated at regularly scheduled intervals.
Total carbohydrate intake should be the focus, but protein and fat intake should also be considered
due to comorbid conditions (e.g., nephropathy, cardiovascular disease) associated with diabetes.
2. The plate method is a tool to provide portion control with healthier food group choices. The con-
cept is to divide and fill a standard-sized dinner plate as follows: half of plate with nonstarchy veg-
etables (e.g., broccoli, salad, cabbage, collards); one-fourth of the plate with meat (3 oz, cooked);
one-fourth of plate with starch (e.g., potatoes, beans, bread, noodles). A serving of fruit may also
be combined with the meal in addition to the plate described (Figure 46-1).
B. Physical activity may be gradually incorporated into daily routines with the goal of at least 150 mins
per week of moderate-intensity aerobic exercise. Muscle strengthening activities should be performed
at least 2 or more days per week.
C. Prevention, recognition, and treatment of acute hypoglycemic and hyperglycemic episodes
should be reviewed at every opportunity.
D. Reduction of modifiable risk factors to minimize or prevent the development of chronic
complications
1. Achievement of glycemic, lipid, and blood pressure goals
2. Smoking cessation
3. Reduction in weight, if appropriate
E. Pattern control to determine effect of sickness, dietary choices, stress, and physical activity on ability
to attain and maintain glycemic goals.
F. Implementation of specific self-care measures
1. Foot care. Peripheral neuropathy and peripheral vascular disease in individuals with T1DM or
T2DM increase the likelihood of developing lower extremity complications and amputations.
Proper foot care is essential to minimize these risks.
a. The feet should be inspected daily, looking for abnormalities (e.g., cuts, sores, blisters, or ir-
ritated areas). Medical attention should be sought if abnormalities are present.
b. Shoes should be properly fitted and free of foreign objects. Shoes should be worn at all times
to avoid trauma to a bare foot.
c. Toenails should be trimmed straight across with the edges filed.
d. Lotions, creams, or ointments applied between the toes may lock in moisture, leading to mac-
eration. Avoid applying these agents between the toes.
2. Dental care. A yearly dental exam is recommended. In the absence of teeth in the adult with
diabetes, examination of the gums is essential due to the high prevalence of periodontal disease
in this population.
3. Eye care. An annual dilated eye exam should be recommended, beginning 5 years after diagnosis
of T1DM and at diagnosis of T2DM. Increased frequency of eye exams may be necessary, depend-
ing on the development and severity of eye disease.
XII. DEVICES FOR DIABETES

A. Syringes
1. Barrel size: Syringes for insulin administration are marked in units. Markings may differ based
on size of insulin syringe barrel chosen. Barrel sizes include 0.25-, 0.3-, 0.5-, and 1.0-mL capacity.

The recommendation of a particular size of insulin syringe should be the smallest capacity size
available for the prescribed dose of insulin:
a. up to 25 units of insulin: 0.25 cc (0.25-mL)
b. up to 30 units of insulin: 0.3 cc (0.30-mL)
c. up to 50 units of insulin:0.5 cc (0.50-mL)
d. up to 100 units of insulin: 1 cc (1.0 mL)
2. Needle length: available as original ½ inch (12.7 mm) and short 5/16 inch (8 mm)
3. Needle gauge simply refers to the “thickness” of the needle and is an inverse relationship (i.e.,
the higher the gauge, the thinner the needle). Typical gauges for insulin administration range
from 28 to 31 gauge. Because higher gauge needles are thinner, they are also more fragile. Thus,
higher gauge needles are typically shorter needles.
B. Insulin pens allow for enhanced portability and eliminate the need for coordination in draw-
ing up a dose of insulin. Most devices are prefilled with insulin and are disposable. It is impor-
tant to note that insulin pens are for single-person use to prevent the spread of blood-borne
illnesses.
1. Devices
a. Solostar (Sanofi Aventis products): glargine (Lantus); glulisine (Apidra)
b. Flexpen (Novo Nordisk products): detemir (Levemir); aspart (Novolog); aspart mix (Novolog
Mix 70/30)
c. Kwikpen (Eli Lilly products): lispro (Humalog); lispro mix (Humalog Mix 50/50, 75/25)
2. Pen needles are available in several lengths:
a. ½ inch (12.7 mm)
b. 5/16 inch (8 mm)
c. 3/16 inch (5 mm)
d. 5/32 inch (4 mm)
C. Home blood glucose monitors. A plethora of meters are available to patients today.
1. Meter selection: Some patients choose meter on size, others on cost, and still others on appear-
ance of the meter. When recommending a meter for an elderly patient, the cost of the meter and
the manual dexterity and vision of the individual should be kept in mind. Children usually do
better with a meter that requires only a minimal amount of blood sample applied to the strip.
Meter choices for the visually impaired have tactile markings on the strip or speech output on
the meter.
2. Alternate site testing has become more prominent in all populations. However, it is not appropri-
ate in all situations.
a. Conditions when alternate site testing may be appropriate include:
(1) In pre-meal or fasting state (% 2 hrs since last meal)
(2) 2 or more hours after taking insulin
(3) 2 or more hours after exercise
b. Alternate site testing should not be used if:
(1) The results from the alternate site do not match how the person feels
(2) Symptoms of hypoglycemia are present.
XIII. SIGNIFICANT DRUG INTERACTIONS AFFECTING GLYCEMIC

CONTROL. This is only a partial list of potential drug interactions that may affect glycemic control.
Consult standard references or drug package inserts for more detailed information.
A. Potential hyperglycemia, as a dose-dependent, direct glucogenic effect. Corticosteroids, nicotinic
acid, phenytoin, pentamidine (long-term effect), protease inhibitors, sympathomimetics, isoniazid,
furosemide, thiazide diuretics
B. Potential hypoglycemia, as a direct hypoglycemic effect; monoamine oxidase (MAO) inhibitors,
fluoxetine, salicylates (large doses), fenfluramine, alcohol, pentamidine (initial effect)
C. Prolonged hypoglycemia and masking of hypoglycemic symptoms. !-Blockers
D. Altered protein binding of, or other drug interaction with, sulfonylurea agents. Alcohol, salicy-
lates, nonsteroidal anti-inflammatory drugs (NSAIDs), methyldopa, chloramphenicol, MAO inhibi-
tors, clofibrate, probenecid

950 Chapter 46
Study Questions
Directions: Each of the questions, statements, or 4. A 222-lb male presents to the diabetes care team for
incomplete statements in this section can be correctly routine diabetes management. His fingerstick blood
answered or completed by one of the suggested answers or glucose value is 452 mg/dL (445 mg/dL on repeat) and
phrases. Choose the best answer. his urine is negative for ketones. Per clinic protocol, he
may be treated in the office for hyperglycemia. Which
1. Which patient meets the diagnostic criteria for
is the most appropriate treatment to bring his blood
diabetes, assuming tests were taken on separate visits?
glucose to a target of 120 mg/dL?
(A) An elderly female with fasting blood glucose
(A) Glargine 20 units
values of 102 mg/dL and 132 mg/dL.
(B) Lispro 60 units
(B) A teenage boy with a fasting blood glucose of
(C) Aspart 30 units
128 mg/dL and an A1c of 6.6%.
(D) Glulisine 11 units
(C) A 10-year-old girl with a random blood glucose
(E) Detemir 24 units
value of 180 mg/dL and 190 mg/dL.
(D) A morbidly obese male with a random blood 5. A 400-lb male has just been diagnosed with type 2
glucose value of 102 mg/dL and an oral glucose diabetes. His A1c is greater than 15% and his kidney
tolerance test result of 160 mg/dL. and liver function are normal. Which would be the
most appropriate initial agent for monotherapy?
2. A 45-year-old obese female has just been diagnosed
with diabetes. Otherwise, she is healthy with no (A) Metformin 850 mg q.d.
other medical conditions. Her blood pressure today (B) Pioglitazone 30 mg q.d.
is 110/75 mm Hg; spot urine microalbumin ' 30; (C) Glargine 36 units q.d.
TC 180; HDL 32; LDL 122; TG 150. Based on ADA (D) Liraglutide 0.6 mg q.d.
guidelines, which should be started today? (E) Glimepiride 4 mg q.d.
(A) Aspirin 81 mg daily 6. An individual with T2DM currently takes
(B) Pravastatin 10 mg daily metformin XR 500 mg 2 b.i.d., pioglitazone 45 mg,
(C) Lisinopril 10 mg daily and glimepiride 4 mg b.i.d. He takes his morning
(D) Irbesartan 150 mg daily medications at 8 a.m. with breakfast and his evening
medications at 6 p.m. with supper. He does not eat
3. A patient is currently on a regimen of Humalog Mix
lunch. He brings in his log book and meter today,
70/30, 24 units in the morning and 12 units in the
which reveal multiple hypoglycemic events (45 to
evening. Based on the following averages obtained
62 mg/dL) around 1 p.m. to 2 p.m. His A1c today
from his blood glucose meter, which would be the
is 6.0%. Which would be the most appropriate
most appropriate recommendation for his glycemic
recommendation for glycemic control at this time?
control today?
(A) Discontinue morning dose of metformin
Pre-Breakfast: 220 mg/dL
(B) Discontinue evening dose of metformin
Pre-Lunch: 110 mg/dL
(C) Discontinue daily dose of pioglitazone
Pre-Supper: 90 mg/dL
(D) Discontinue morning dose of glimepiride
Bedtime: 108 mg/dL
(E) Discontinue evening dose of glimepiride
3 am: 62 mg/dL
(A) Increase evening dose of Humalog Mix to 7. A 64-year-old female is taking metformin,
15 units pioglitazone, and sitagliptin for T2DM. Her liver
(B) Decrease evening dose of Humalog Mix to function tests were elevated (AST 132 u/L and ALT
10 units 140 u/L) and she tested positive for Hepatitis C.
(C) Continue current regimen without changes Which is the best recommendation at this time?
(D) Increase morning dose of Humalog Mix to (A) Discontinue metformin only
28 units (B) Discontinue pioglitazone only
(E) Decrease morning dose of Humalog Mix to (C) Discontinue sitagliptin only
20 units (D) Discontinue metformin and pioglitazone
(E) Discontinue all agents for glycemic control

8. Which best describes the mechanism of action of 13. A patient presents for treatment of his type 2 diabetes
repaglinide? mellitus (T2DM). His A1C is 7.2% and he has
(A) Insulin secretagogue hepatitis C (AST " 150 units/L; ALT " 132 units/L),
(B) Insulin sensitizer hypertension, dyslipidemia, rheumatoid arthritis, and
(C) DPP-IV inhibitor mild renal impairment (SCr " 1.6). Which would be
(D) GLP-1 agonist the best initial agent at this time?
(E) *-glucosidase inhibitor (A) saxagliptin
(B) metformin
9. A patient has been hospitalized for the past 3 days
(C) pioglitazone
following a severe asthma exacerbation, but is being
(D) glulisine
discharged today. He weighs 228 lb, but he has no
previous history of diabetes. Blood work today shows 14. An obese woman (350 lb) has used metformin
a random blood glucose of 320 mg/dL and an A1c of 1000 mg bid to control her T2DM for the past 2 years.
5.2%. His current medication list includes albuterol Her A1C today is 8%. Which would be the most
nebules, prednisone, pulmicort, and oxygen. Which appropriate recommendation to improve glycemic
statement is most appropriate? control without providing further weight gain?
(A) The patient has diabetes and should be discharged (A) sulfonylurea
on an insulin regimen. (B) thiazolidinedione
(B) The patient has hyperglycemia induced by his (C) GLP-1 agonist
inhaled corticosteroid. (D) amylin agonist
(C) The patient has hyperglycemia induced by his
15. All of the following are correct statements about
! agonist.
metformin except
(D) The patient has hyperglycemia induced by his
oral glucocorticoid. (A) metformin may cause renal impairment.
(B) metformin should not be used in patients who
10. A patient currently takes Amaryl, Actos, Januvia, and are alcoholic.
Lantus. He presents to the clinic today concerned (C) metformin should be discontinued in women
about the swelling in his lower extremities, significant with a SCr % 1.4.
weight gain, and shortness of breath. Which is the (D) metformin may cause vitamin B12 depletion.
most likely cause of presenting symptoms?
16. A patient takes neutral protamine Hagedorn (NPH)
(A) Amaryl
16 units bid and regular insulin 6 units bid. Based on
(B) Actos
her average blood glucose values below, what is the best
(C) Januvia
recommendation for adjusting her insulin regimen?
(D) Lantus
(A) fasting: 82 mg/dL
11. A person newly diagnosed with T1DM will need (B) pre-lunch: 180 mg/dL
to start an insulin regimen. Based on her weight of (C) pre-supper: 110 mg/dL
100 lb, which would be the most appropriate basal (D) bedtime: 98 mg/dL
regimen?
17. A patient has been using continuous intravenous insulin
(A) Levemir 13 units daily
infusion at 0.8 units/hr with steady control after being
(B) Lantus 27 units daily
diagnosed with type 1 diabetes mellitus (T1DM). He is
(C) Novolog 4 units three times daily
to be discharged from the hospital with prescriptions
(D) NPH 15 units once daily
for detemir and glulisine. When is the most appropriate
(E) U-500 1.5 mL twice daily
time to initiate the detemir?
12. Which formulation is the best recommendation for a (A) 30 minutes prior to discontinuing the continuous
patient needing an intravenous insulin infusion? insulin infusion
(A) Regular insulin, U-500 (B) 1 hour prior to discontinuing the continuous
(B) Regular insulin, U-100 insulin infusion
(C) NPH insulin, U-100 (C) 2 hours prior to discontinuing the continuous
(D) Aspart insulin, U-100 insulin infusion
(E) Aspart insulin, U-400 (D) 1.5 hours after discontinuing the continuous
insulin infusion
(E) 3 hours after discontinuing the continuous
insulin infusion

952 Chapter 46
Answers and Explanations

1. The answer is B [see III.B]. 6. The answer is D [see V.B.1.a; Table 46-3].
Regardless of age or gender, diagnostic criteria for dia- The pharmacologic agent most responsible for causing
betes in the nonpregnant individual is a positive of at hypoglycemia is the sulfonylurea (glimepiride), which
least two of the following values: random blood glu- is compounded by the fact that the patient does not eat
cose % 200 mg/dL; fasting blood glucose & 126 mg/ lunch. The morning dose of glimepiride would peak
dL; OGTT & 200; A1c & 6.5%. around lunch time when food intake should be occur-
ring. In the absence of lunch, hypoglycemia results.
2. The answer is B [see X.A.1].
Based on ADA guidelines, aspirin should be initiated 7. The answer is D [see V.C.3.b; V.D.3.a; V.F].
for primary prevention in women greater than age Metformin and pioglitazone should not be used in a
60; statin therapy should be initiated in patients with patient with liver disease and elevated LFTs. Sitagliptin
overt CVD or any patient over the age of 40 without may be used in hepatic impairment. When the LFTs go
overt CVD, but with other CVD risk factors; ACEI and back to a normal range, it can be considered to reiniti-
ARBs are recommended for blood pressure control if ate metformin and pioglitazone.
necessary (not needed here) and when urine microal-
8. The answer is A [see V.B.1.b].
bumin is % 30.
Repaglinide is a meglitinide, which works to produce a
3. The answer is B [see Table 46-2; V.A.8.b]. rapid burst of insulin secretion from the pancreas.
Increasing the morning dose will only lower the lunch
9. The answer is D [see III.B; XIII.A].
and supper readings further. Increasing the evening
Inhaled corticosteroids have no effect on the blood glu-
dose will lower the 3 a.m. even more. This patient is most
cose of an individual without diabetes and ! agonists
likely experiencing rebound hyperglycemia (Symogyi)
have no effect. However, oral steroids, such as predni-
as evidenced by the hypoglycemia at the 3 a.m. readings
sone can induce significant hyperglycemia, particu-
and elevated fasting readings pre-breakfast.
larly in the midafternoon when dosed in the morning.
4. The answer is D [see V.A.7.a].
10. The answer is B [see V.D.6.a; Table 46-3].
The blood glucose needs to come down rapidly in-
Patients taking a TZD such as Actos should be moni-
office, thus he would not choose glargine or detemir
tored for peripheral edema, weight gain, and shortness
as agents due to their longer onset of action. Lispro,
of breath due to its propensity to cause or worsen heart
aspart, and glulisine would all be appropriate choices,
failure.
but the dose should be based on the point-of-care cor-
rection equation ([Current blood glucose-Target blood 11. The answer is A [see V.A.6.a].
glucose]/CF). Steps to solve: NovoLog is not a basal insulin and U-500 is reserved
for patients with severe insulin resistance. NPH is
1. Weight in kg: Weight is 222lb " 101 kg
dosed twice daily. Basal insulin should be initiated at
2. Determine TDD: (101)(0.6) " 60
50% of TDD. TDD is 27 units, which gives 13.5 units
3. Determine CF: 1800/60 " 30
as basal.
4. Plug into equation: (452–120)/30 " 11 units
12. The answer is B [see V.A.9.b].
5. The answer is C [see VI.A.1.c].
Regular insulin, U-100 is the most logical choice for an
Metformin would typically be the initial agent of choice
IV infusion. Aspart may be given in an emergency pre-
in a patient diagnosed with type 2 diabetes. However,
paredness situation, but should not be given routinely
with this patient’s A1c greater than 15%, insulin is the
due to the additional cost above that of regular U-100
most appropriate choice. Metformin can be started in
insulin.
addition to the insulin, but not as monotherapy. Oral
agents and non-insulin injections will bring the A1c 13. The answer is A [see V.F.2; VI.A.1.a].
down no greater than 1%. Metformin and pioglitazone should not be used in liver
impairment and metformin must be used cautiously
in renal impairment. Rapid acting insulin would help
with postprandial blood glucose values, but is not con-
sidered a standard recommendation for initial insulin
therapy in T2DM. Saxagliptin may be used in patients
with hepatic and renal impairment.

14. The answer is C [seeV.B.6.b; V.D.6.a; Table 46-3]. 16. The answer is B [see V.A.8; Table 46-2].
Both sulfonylureas and TZDs have the potential to Increasing morning NPH will cause further decrease
increase weight, whereas GLP-1 agonists and amylin of pre-supper reading. Increasing evening doses of in-
agonists can provide weight loss. Amylin agonist is sulin will cause fasting blood glucose to be too low.
not appropriate because it should only be added after a
17. The answer is C [see V.A.9.b.(2)].
basal and bolus insulin have been added.
Long-acting insulin should be injected 2 hours prior
15. The answer is A [see V.C.3.a]. to discontinuation of a continuous insulin infusion to
Metformin should not be used in patients with renal allow adequate onset time.
disease, but the metformin itself does not cause renal
impairment.

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46 Diabetes Mellitus

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II. PATHOPHYSIOLOGY OF THE DIABETIC STATE

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III. CLINICAL EVALUATION

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(8) Previous testing indicative of prediabetes

V. PHARMACOLOGIC TREATMENT OF DIABETES MELLITUS

Table 46-1 GUIDELINE RECOMMENDATIONS FOR OUTPATIENT GLYCEMIC

American Diabetes American Association of Clinical

A1c goal ' 7.0% ( 6.5%

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Table 46-2 TYPES OF INSULIN—ONSET, PEAK, AND DURATION OF ACTIONa

Effective Variability in Absorption

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8. Insulin adjustments for repeated, time-sequenced events of hypoglycemia or hyperglycemia: When

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b. Meglitinides: Repaglinide (Prandin)

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Table 46-3 ORAL AND NONINSULIN INJECTABLE AGENTSa

Agent Initial Dose (Maximum Dose) Comments

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Table 46-3 Continued.

Agent Initial Dose (Maximum Dose) Comments

Bile Acid Sequestrants

Colesevelam (Welchol) 1.875 g (3 tablets) b.i.d. or 3.75 g Adjunctive treatment only

(Continued on next page)

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Table 46-3 Continued.

Agent Initial Dose (Maximum Dose) Comments

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6. Patient education and other concerns

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4. Mechanism of action for improved glycemic control is unknown.

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VI. GLYCEMIC MANAGEMENT OF T2DM

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VII. PHARMACOLOGIC THERAPY OF PREDIABETES. Therapy with data to delay

VIII. HYPERGLYCEMIC EMERGENCIES. The two most common hyperglycemic emergencies

Table 46-4 RECOGNITION OF DKA AND HHS3

Onset Sudden Gradual

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XI. PATIENT EDUCATION AND SELF-CARE. Education and development of self-

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Figure 46-1. The plate method.

XII. DEVICES FOR DIABETES

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XIII. SIGNIFICANT DRUG INTERACTIONS AFFECTING GLYCEMIC

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Answers and Explanations

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