Diabetes Mellitus - ACCP

Diabetes Mellitus

ACCP Updates in Therapeutics® 2012: The Ambulatory Care Pharmacy Preparatory Review and Recertification Course

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Diabetes MellitusMichael P. Kane, Pharm.D., FCCP, BCPS, BCACP

Albany College of Pharmacy and Health SciencesThe Endocrine Group, LLP

Albany, New York

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Learning Objectives:

1. Demonstrate an understanding of the normal regu-lation of blood glucose with respect to the actions of insulin, cortisol, growth hormone, glucagon, and incretins in glucose homeostais.

2. Identify differences between prediabetes, type 1 diabetes mellitus (DM), type 2 DM, and gesta-tional diabetes, including differences in diagnostic criteria and clinical presentaton.

3. Explain sick-day rules for a patient with diabetes.4. Compare agents used in the treatment of DM, in-

cluding their mechanisms of action, adverse ef-fects, contraindications, and overall effectivenss.

5. Select appropriate insulin regimens for patients based on desired onset, peak, and duration of insulin effets.

6. Individualize a comprehensive glycemic treatment and monitoring plan for a patient withDM.

7. State appropriate lipid and blood pressure targets for patients with diabetes.

8. Discuss short- and long-term complications associ-ated with diabetes as well as strategies to prevent or slow their progression.

Self-Assessment QuestionsAnswers and explanations to these questions may be found at the end of the chapter.

E.G. is a 65-year-old Hispanic American man with a history of inflammatory bowel disease and a 6-year his-tory of type 2 diabetes mellitus (DM) who presents to your pharmacy with a new prescription. After an ini-tial 6-month trial of diet and exercise, he was placed on metformin. He has tolerated the drug well, but he has noticed an increase in his hemoglobin A1c (A1c) during the past 6 months. A review of blood glucose readings reveals a record of fasting blood glucose (FBG) values in the range of 100–120 mg/dL and premeal blood glu-cose values of 180–200 mg/dL. In addition, today’s blood work included the following information:

A1C 7.9%; fasting lipids: total cholesterol (TC) 178; low-density lipoprotein cholesterol (LDL-C) 68; high-density lipoprotein cholesterol (HDL-C) 51; triglycerides (TG) 145; AST (aspartate aminotransferase) 28 (5–30) ALT (alanine aminotransferase) 35 (5–40)

142 101 19156

4.4 28 1.2

9.114.0

20843.1

1. Which one of the following is the most appropriate therapy for E.G.?A. Discontinue metformin (Glucophage) because

of poor renal function, and add basal/bolus insulin.

B. Add glargine (Lantus) insulin 10 units subcutaneously at bedtime to his current regimen.

C. Add sitagliptin (Januvia) 100 mg orally every day to his current regimen.

D. Add acarbose (Precose) 100 mg orally 3 times/day to his current regimen.

C.A. is a 75-year-old white man with a 55-year history of type 1 DM. He presently receives regular insulin and neu-tral protamine Hagedorn (NPH) insulin twice daily (be-fore breakfast and supper), for a total daily insulin dose of 30 units. He tests his blood glucose just before meals and at bedtime. There have been no substantial changes in diet, exercise, stress, or illness during this time.

7 a.m. Noon 5 p.m. 10 p.m.Wednesday 97 115 157 116Thursday 100 109 149 118Friday 95 110 153 110Saturday 105 111 160 115Sunday 107 106 154 111

2. Given the above blood glucose values, which one of the following choices is best to make?A. Add a noontime regular insulin dose.B. Increase the morning regular insulin.C. Increase the morning NPH insulin.D. Increase the evening regular insulin.

E.H. is a 53-year-old man with a body mass index (BMI) of 30.5 kg/m2. He was given a diagnosis of type 2 DM 5 years ago, and he has been taking oral antihy-perglycemic agents for almost 5 years. Because E.H.’s hemoglobin A1c has increased to 9.1%, his medical provider recommended that he begin Humalog 75/25,

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40 units 2 times/day. Three months later, E.H.’s A1c is down to 7.3%, but he is having hypoglycemic episodes midmorning almost daily. His blood glucose logs show FBG values in the near-normal range.

3. Which one of the following is the most appropriate adjustment to E.H.’s therapy?A. 60 units of insulin glargine daily and 8 units

of insulin aspart at meals.B. 48 units of insulin glargine daily and 8 units

of insulin aspart at meals.C. 32 units of insulin glargine daily and 8 units

of insulin aspart at meals.D. 16 units of insulin glargine daily and 8 units

of insulin aspart at meals.

4. Which one of the following options most appropri-ately lists insulins in order from most rapid acting to longest acting?A. Apidra, Lantus, Levemir, NovoLog.B. Humalog, Levemir, NPH, Apidra.C. NovoLog, Regular, Levemir, Lantus.D. Lantus, Apidra, Humalog, Levemir.

5. Pramlintide and exenatide both primarily reduce postprandial blood glucose levels. Which one of the following activities best differentiates exena-tide’s mechanisms of action from pramlintide’s? A. The ability to cause a glucose-dependent

increase in insulin secretion.B. The ability to cause a glucose-dependent

decrease in glucagon secretion.C. The ability to increase satiety.D. The ability to reduce the rate of postmeal

carbohydrate absorption.

6. A.B. is an 84-year-old woman who lives alone. She was given a diagnosis of type 2 DM 2 years ago. Yesterday’s A1c is reported back today as 8.0%. The only other noteworthy laboratory value is a serum creatinine of 1.3 mg/dL. She and her family are very concerned about hypoglycemia in anticipa-tion of A.B.’s starting diabetes medication. Which one of the following medications is best for A.B.?A. Glyburide.B. Metformin.

C. Nateglinide.D. Sitagliptin.

7. P.D. is a 40-year-old nonhypertensive patient with a 25-year history of type 1 DM. Results of the past two urine analyses have revealed micro-albuminuria. Which one of the following interven-tions is best to slow the progression of P.D.’s diabetic nephropathy?A. Aspirin use.B. Angiotensin-converting enzyme inhibitor

(ACEI) use.C. High-protein diet.D. Dihydropyridine–calcium channel blocker

(DHP-CCB) use.

8. Which one of the following diabetes-related com-plications is the most relevant goal of the “ ABC’s approach” to diabetes management?A. Retinopathy.B. Nephropathy.C. Peripheral neuropathy.D. Macrovascular disease.

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I. DIABETES MELLITUS

A. Clinical Pearls1. Insulin decreases glucose; all other hormones increase blood glucose (e.g., growth hormone, cortisol,

epinephrine, thyroid, glucagon).2. Diabetes management: It is all about the food!3. The bigger they are (A1c), the harder they fall.4. With oral therapy, add, do not substitute, therapies.5. Diabetes management: It is more than just (treating) blood glucose.6. Diabetes is a cardiovascular disease (CVD) risk equivalent.7. Fix the fasting (glucose) first.8. Fifty percent of patients with type 2 DM present with end-organ damage at the time of diagnosis.

B. Guidelines1. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation

and Adjustment of Therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203.

2. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on Type 2 Diabetes Mellitus: an algorithm for glycemic control. Endocr Pract 2009;15:540–59.

3. American Diabetes Association. Standards of medical care in diabetes – 2011. Diabetes Care 2011;34(Suppl 1):S11–S61.

4. Rodbard HW, Blonde L, Braithwaite SS, et al; AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists’ medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007;13(Suppl 1):1–68.

5. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011;17(Suppl 2):1–53.

C. Helpful Web sites1. www.diabetes.org2. www.cdc.gov/diabetes/3. www.idf.org4. www.jdf.org5. www.diabetes.ca6. www.diabetes.niddk.nih.gov/7. www.guidelinecentral.com/guidelines-author/american-college-of-endocrinology-guidelines

D. Classification1. Type 1 DM (insulin-dependent, juvenile onset, ketosis prone): Absolute insulin deficiency typically

caused by B-cell destruction; immune mediated and idiopathic; 95% with genetic marker of human leukocyte antigen DR3 and/or DR4; latent autoimmune diabetes in adults (LADA)or type 1½ DM

2. Type 2 DM (non–insulin-dependent, adult onset): 90%–95% of all diabetes cases; insulin resistance with progressive insulin secretory defect (insulin deficiency); adults may be asymptomatic for years (50% present with diabetes-related complication at time of diagnosis); disturbing trend of diagnosis in adolescents and children. Risk factors:a. First-degree relative with type 2 DMb. Overweight (BMI 25–29.9 kg/m2) or obesity (BMI of 30 kg/m2 or more)

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c. African, Hispanic, or Native American ethnicityd. Physical inactivitye. History of gestational DM or birth of a 9-lb or greater babyf. History of prediabetesg. History of hypertension (HTN)h. History of high TG (more than 250 mg/dL)i. History of low HDL-C (less than 35 mg/dL) valuesj. History of polycystic ovary syndrome (PCOS)k. History of CVD

3. Gestational DM: Diabetes diagnosed during pregnancy; represents about 7% of all pregnancies (ranging from 1% to 14%, depending on the population studied and the diagnostic tests employed), resulting in more than 200,000 cases annually. Women should undergo glucose testing at the first prenatal visit if known to have a risk factor; otherwise, between 24 and 28 weeks. Risk factors include those listed above (risk factors for type 2 DM).

4. Othera. Drug-induced: Pentamidine, glucocorticoids, nicotinic acid, interferon alfa, diazoxide,

hydrochlorothiazide, atypical antipsychotics, protease inhibitorsb. Endocrinopathies: Acromegaly, Cushing syndrome, pheochromocytomac. Genetic defects of B-cell function or insulin function: MODY (maturity-onset diabetes of the

young), leprechaunism, Rabson-Mendenhall syndromed. Pancreatic exocrine disease: Pancreatitis, trauma, infection, cystic fibrosis, hemochromatosis

E. Diagnosis. Diagnosis is based on glycemic levels, below which there was little prevalent retinopathy and above which the prevalence of retinopathy increased in a curvilinear fashion; need two positive tests (preferably the same test) on 2 different days:1. Fasting plasma glucose (FPG) of 126 mg/dL or more (no caloric intake for at least 8 hours)

(prediabetes: FPG of 100–125 mg/dL)2. 75-g oral glucose tolerance test (OGTT), 2-hour glucose level of 200 mg/dL or more; less false

negatives than FPG but more expensive and more difficult to perform (prediabetes: OGTT of 140–199 mg/dL)

3. Symptoms of DM (polyuria, polydipsia, weight loss, sometimes with polyphagia, blurred vision) with a casual blood glucose of 200 mg/dL or greater

4. Hemoglobin A1c of 6.5% or greater; some controversy exists; analyses of NHANES data indicate that, assuming universal screening of the undiagnosed, the A1c cut-off point of 6.5% or greater identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut point of 126 mg/dL or above; however, the wider application of a more convenient test (A1c) may actually increase the number of diagnoses made. Point-of-care A1c assays are not sufficiently accurate at this time to use for diagnostic purposes (prediabetes: A1c 5.7%–6.4%).

5. Diagnosis of gestational DM – New criteria as of 2011a. Screen between weeks 24 and 28 of gestation if no diabetes risk factors; screen at first prenatal visit

in a patient with even one diabetes risk factor, and if normal, repeat between weeks 24 and 28.b. Screen using a 75-g 2-hour OGTT using the diagnostic cut points listed below (measurements

convey an odds ratio of adverse maternal, fetal, or neonatal outcome of at least 1.75 compared with glucose levels below the listed cut points). Two-step screening is no longer recommended; one abnormal blood glucose result makes the diagnosis. Women with a history of gestational DM should be screened for diabetes 6–12 weeks postpartum using non-pregnant OGTT criteria (and lifelong screening, at least every 3 years).

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Table 1. Gestational DM OGGT Diagnostic Cutpoints

75-g Glucose Load (mg/dL)Fasting 921 hour 1802 hour 153

DM = diabetes mellitus; OGTT = oral glucose tolerance test.

Patient Case1. An obese 50-year-old Hispanic American woman with a history of gestational DM presents to the clinic for

her annual physical examination. Her family history is significant for type 2 DM in her parents, both sets of grandparents, and several aunts and uncles. An FPG is 160 mg/dL. She has no concerns. Which one of the following best conveys how this patient should be medically managed?A. Rescreen in 3 years.B. Obtain another FPG level next week.C. Order an OGTT before she leaves her appointment.D. Diagnose type 2 DM and initiate lifestyle changes.

F. Screening1. Type 1—Only if symptomatic. One may consider screening if one has a first-degree relative with

type 1 DM (blood test for islet cell antibodies, insulin antibodies, and/or glutamic acid decarboxylase antibodies).

2. Type 2—Testing in all adults 45 years and older; consider testing earlier if overweight or obese with one or more of the following risk factors: physically inactive, first-degree relative with DM, high-risk ethnic population (African, Hispanic, or Native American ethnicity), history of gestational DM or birth of 9-lb or greater baby, history of prediabetes, HTN, high TG (more than 250 mg/dL) or low HDL-C (less than 35 mg/dL) values, history of PCOS, history of vascular disease.

3. Gestational DM—See above under Diagnosis.

G. Prediabetes1. Diagnosis—See above. An estimated 57 million Americans have prediabetes, which places them at

high risk of developing diabetes, although interventions during prediabetes may prevent it.2. Interventions for the prevention of diabetes in patients with prediabetes

a. Weight loss of 7%b. Increase in physical activity to at least 150 minutes/week of moderate activity (such as walking)c. Follow-up counseling appears to be important for success.d. Metformin may be considered in those who are at very high risk of developing diabetes (other risk

factors such as A1c greater than 6%, HTN, low HDL-C, elevated TG, or family history of diabetes in a first-degree relative) and who are obese and younger than 60 years. α-Glucosidase inhibitors, orlistat, and thiazolidinediones also delay the onset of type 2 DM, although there are no U.S. Food and Drug Administration (FDA) label-approved drugs for the prevention of diabetes.

e. Recommended to monitor for the development of diabetes annually

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H. Diabetes Pathophysiology1. Type 1 DM: Autoimmune process; destruction of insulin-secreting B cells2. Type 2 DM

a. Overview of defectsi. Relative insulin deficiencyii. Insulin resistanceiii. Increased hepatic glucose productioniv. Increased gastric emptying ratev. Neuroendocrine dysfunction

(a) Decreased amylin secretion(b) Impaired incretin effect

b. The Ominous Octet (DeFronzo RA. Diabetes 2009;58:773–95)i. There are many cellular defects in type 2 DM.

(a) B cell—Insulin deficiency (relative or absolute)(b) Muscle—Insulin resistance(c) Liver—Increased gluconeogenesis(d) Fat cell (adipocytes)—Accelerated lipolysis(e) Gastrointestinal (GI) tract—Incretin deficiency (glucagon-like peptide) and/or resistance

(glucose-dependent insulinotropic polypeptide)(f) Alpha cell—Hyperglucagonemia(g) Kidney—Increased glucose absorption(h) Brain—Neurotransmitter dysfunction

ii. Take-home points(a) Type 2 DM is a multi-pathophysiologic disease.(b) Combination therapy: Many drugs will be required to correct several pathophysiologic defects.(c) Treatment should be based on reversal of known pathogenic abnormalities (not just on

reducing the A1c).(d) Therapy must be started early to prevent/slow the progressive nature of the disease.

I. Treatment Goals1. Eliminate symptoms (e.g., polyuria, polydipsia, fatigue).2. Prevent short-term complications.

a. Hypoglycemiab. Diabetic ketoacidosis/hyperglycemic hyperosmolar state

3. Prevent long-term complications (see below).4. Attain glycemic goals.

a. Patient-specificb. Hemoglobin A1c of 7% or less (American Diabetes Association [ADA]) or 6.5% or less (American

College of Endocrinology/American Association of Clinical Endocrinologists [ACE/AACE])i. Preprandial blood glucose: 70–130 mg/dL (ADA); less than 110 mg/dL (ACE/AACE)ii. Postprandial blood glucose (2 hours after initiation of meal): Less than 180 mg/dL (ADA); less

than 140 mg/dL (ACE/AACE)iii. All recommendations are general guidelines – Always consider each patient on individual basis.

Examples:(a) A 42-year-old, otherwise healthy patient taking metformin and pioglitazone: Goal A1c is less

than 6.5%.(b) An 80-year-old, patient post–myocardial infarction on insulin therapy: Goal A1c is less than 8%.

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J. Treatment1. Nonpharmacologic treatment

a. Medical nutrition therapy (Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K. The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care 2002;25:608–13)

b. Physical activity (Colberg SR, Albright AL, Blissmer BJ, et al. American College of Sports Medicine; ADA. Med Sci Sports Exerc 2010;42:2282–303)i. At least 150 minutes/week of moderate intensity aerobic physical activity (50%–70% of

maximum heart beat) ORii. 90 minutes/week of vigorous aerobic activity (more than 70% of maximum heartbeat)iii. Done at least 3 days/week without doing 2 consecutive days in a rowiv. Resistance exercise is recommended for patients with type 2 DM 3 times/week.

2. Pharmacologic treatmenta. Oral therapies

i. Sulfonylureaii. Metforminiii. α-Glucosidase inhibitoriv. Thiazolidinedionev. Meglitinidevi. Dipeptidyl peptidase-4 inhibitorvii. Resin binderviii. Bromocriptine

b. Parenteral therapiesi. Amylin analogii. Incretin mimeticsiii. Insulin (basal, bolus, mixed)

3. Sulfonylureasa. Mechanism of action: Binds to a sulfonylurea receptor on the B cell. This closes an adenosine

triphosphate–dependent potassium channel, which depolarizes the cell membrane and opens a calcium channel, with the resulting increase in intracellular calcium concentration causing insulin to be released.

b. Efficacy: The bigger they are, the harder they fall!i. Hemoglobin A1c lowering of 1%–2%ii. Reduces fasting and postprandial blood glucose values (mixed effect)iii. Fifty percent of maximal dose begets 80% of drug efficacy.iv. A 5%–10% primary (patient does not respond to therapy) failure rate; 5%–10%/year

secondary (subsequent loss of response to therapy after an initial response) failure ratec. Dose:

i. First-generation agents seldom used (acetohexamide, chlorpropamide, tolazamide, tolbutamide)ii. Glyburide (DiaBeta, Micronase): 5–20 mg/day (as once or twice daily)iii. Glipizide (Glucotrol, Glucotrol XL): 5–20 mg/day (taken once [XL] or 2 times/day);

sulfonylurea of choice in renal insufficiencyiv. Glimepiride (Amaryl): 1–8 mg/day (as once daily)v. Titrate dose weekly.

d. Adverse effects:i. Hypoglycemiaii. Weight gainiii. Less common: Rash, photosensitivity, dyspepsia, nausea

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e. Contraindications:i. Hypersensitivityii. Diabetic ketoacidosisiii. Type 1 DMiv. Severe liver or kidney disease (glipizide recommended in renal insufficiency)v. Hypoglycemic unawareness

f. Advantages:i. Works quickly (within hours)ii. High initial response rateiii. Inexpensive

g. Disadvantages:i. Hypoglycemiaii. Weight gainiii. Eventual treatment failureiv. Cardiovascular concerns?

4. Biguanide – Metformin (Glucophage, Riomet, Glucophage extended release [XR], Glumetza, Fortamet)a. Mechanism of action:

i. Primarily inhibits hepatic glucose productionii. Secondarily some improvement of peripheral insulin resistanceiii. May decrease intestinal absorption of glucose (small intestine)

b. Efficacy:i. Hemoglobin A1c lowering of 1%–2%ii. Primarily reduces FBGiii. A 5%–10% per year secondary failure rate

c. Dose:i. 500 mg once or twice daily with food to start (decrease GI adverse effects); increase dose by

500 mg/day at weekly intervalsii. Maximal dose: 2550 mg/dayiii. Common dose: 1 g twice daily (or 2 g at bedtime with an XR product)

d. Adverse effects:i. Common: Nausea, vomiting, diarrhea (especially early)ii. Uncommon: Macrocytic anemia (caused by vitamin B12 deficiency); lactic acidosis

(uncommon but life threatening! Use only in appropriate patients)e. Contraindications:

i. Serum creatinine of 1.5 mg/dL or greater in men; serum creatinine of 1.4 mg/dL or greater in women

ii. Creatinine clearance (CrCl) less than 50 mL/minute?iii. Severe hepatic, pulmonary, or cardiac diseaseiv. Intravascular contrast studies with iodinated materials can lead to acute alteration of renal

function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients for whom any such study is planned, Glucophage or Glucophage XR should be temporarily discontinued at the time of or before the procedure and withheld for 48 hours after the procedure and reinstituted only after renal function has been reevaluated and found to be normal (Glucophage PI).

f. Advantagesi. Improved CV outcomes? (UK Prospective Diabetes Study [UKPDS] of obese patients)ii. No hypoglycemia as monotherapyiii. Weight neutral

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iv. High initial response ratev. Positive lipid effectsvi. Inexpensive

g. Disadvantagesi. Patients eventually stop responding to therapy.ii. Gastrointestinal adverse effects early

5. Meglitinidesa. Mechanism of action: Similar to sulfonylurea (but stimulates meglitinide receptor)b. Efficacy:

i. Hemoglobin A1c reduction of 0.5%–1% (Repag > Nateg) as monotherapy or add-on therapy; A1c reductions of 1.5%–1.8% in combination with metformin or thiazolidinedione

ii. Reduces postprandial blood glucoseiii. Mealtime (e.g., 3 times/day) dosing (may reduce adherence)

c. Dose:i. Repaglinide (Prandin): 0.5–1 mg 1–15 minutes before meals; maximal daily dose 16 mgii. Nateglinide (Starlix): 60 or 120 mg before meals

d. Adverse effects:i. Hypoglycemia (< sulfonylurea)ii. Modest weight gain (< sulfonylurea)

e. Contraindications:i. Diabetic ketoacidosisii. Type 1 DMiii. Hypoglycemic unawarenessiv. Repaglinide and gemfibrozil

f. Advantagesi. Rapid onset of actionii. Less hypoglycemia and weight gain compared with sulfonylureaiii. Targets postprandial glucose

g. Disadvantagesi. Hypoglycemiaii. Weight gainiii. Eventual treatment failure

6. α-Glucosidase inhibitorsa. Mechanism of action: Inhibits the enzyme α-glucosidase, found along the brush border of the small

intestine, which is responsible for the breakdown of complex carbohydrates into glucose, thus delaying and reducing postmeal carbohydrate absorption and postprandial blood glucose levels

b. Efficacy:i. Hemoglobin A1c reduction of 0.5%–1%ii. Reduces postprandial blood glucoseiii. Mealtime (e.g., 3 times/day) dosing (may reduce adherence)

c. Dose:i. Acarbose (Precose): 25 mg with first bite of meal; start once daily and then increase weekly to

2 times/day; then 3 times/day with meals to decrease GI adverse effects; typical maintenance dose of 50–100 mg with meals; maximum daily dose for 60 kg or less is 50 mg 3 times/day; greater than 60 kg is 100 mg 3 times/day

ii. Miglitol (Glyset): 25 mg with first bite of meal; start once daily and then increase weekly to 2 times/day; then 3 times/day with meals to decrease GI adverse effects; typical maintenance dose of 50 mg with meals; maximum daily dose is 100 mg 3 times/day

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d. Adverse effects:i. Common: Flatulence, abdominal discomfort, diarrhea; occur in up to 80% of patients but may

diminish after 4–8 weeks of therapyii. Rare: Liver function test (LFT) elevation

e. Contraindications:i. Inflammatory bowel diseaseii. Intestinal obstructioniii. Malabsorptioniv. Creatinine clearance less than 25 mL/minute or serum creatinine greater than 2 mg/dLv. Cirrhosis

f. Advantagesi. No hypoglycemia as monotherapy (Note: Use only simple sugar [e.g., glucose] to treat

hypoglycemia in patient receiving combination therapy.)ii. Weight neutral

g. Disadvantagesi. Modest efficacyii. Poorly tolerated GI adverse effectsiii. Need for slow titration

7. Thiazolidinedionesa. Mechanism of action: Peroxisome proliferator–activated receptor-gamma agonist; results in

an increase in insulin-dependent glucose disposal (insulin sensitivity) in skeletal muscle and adipocytes (primarily) and a decrease in hepatic glucose production (secondarily)

b. Efficacy:i. Hemoglobin A1c lowering of 0.8%–1.5%ii. Mixed blood glucose–lowering effectiii. Long lag time before observe glycemic effect (weeks); maximal effect 8–12 weeksiv. Increases HDL-C (both) and lowers TG (pioglitazone)

c. Dose:i. Pioglitazone (Actos)—Dose: 15–45 mg once dailyii. Rosiglitazone (Avandia)—Dose: 1–2 mg/day, up to 8 mg/day (although twice-daily dosing is

more effective); September 23, 2010: FDA restricted access program – The new restrictions are part of a Risk Evaluation and Mitigation Strategy (REMS)—a program required by the FDA to manage serious risks of some marketed drugs. The restrictions are based on data that suggested an elevated risk of heart attacks in patients treated with rosiglitazone.

d. Adverse effects:i. Weight gainii. Fluid retention (most commonly seen with concomitant insulin, nonsteroidal anti-

inflammatory drug, glucocorticoid, or DHP-CCB use)iii. Heart failure exacerbationiv. “Atypical” (hands and feet) bone fractures (pioglitazone) in womenv. Potential myocardial infarctions (rosiglitazone)vi. Rare hepatotoxicityvii. Concern of potential cause of bladder cancer

e. Contraindications:i. Alanine aminotransferase greater than 2.5 times the upper limits of normalii. Class III and IV heart failure

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f. Advantagesi. No hypoglycemia as monotherapyii. Several favorable metabolic effectsiii. Can use in renal insufficiencyiv. Potential β-cell sparing (maintain viability of β-cell function) effect?v. Can induce ovulation in women with PCOS

g. Disadvantagesi. Delayed onset of actionii. Adverse effects (see above)iii. Periodic LFT monitoring recommendediv. Can induce ovulation in women with PCOS

8. Dipeptidyl peptidase-4 inhibitorsa. Mechanism of action: Inhibits the enzyme dipeptidyl peptidase-4 from breaking down endogenous

glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, resulting in increased endogenous incretin levels. This results in a i. Glucose-dependent increase in insulin secretionii. Glucose-dependent inhibition of glucagon secretion

b. Efficacy:i. Hemoglobin A1c lowering of 0.6%–0.8%ii. Reduces primarily postprandial glucose

c. Dose:i. Sitagliptin (Januvia): 100 mg once daily; decreased dosage in renal insufficiency: 50 mg/day

for CrCl 30–50 mL/minute; 25 mg/day for CrCl less than 30 mL/minuteii. Saxagliptin (Onglyza): 5 mg once daily; decreased dosage in renal insufficiency: 2.5 mg/day

for CrCl less than 50 mL/minuteiii. Linagliptin (Tradjenta): 5 mg once daily; no dosage adjustment required in renal or hepatic

insufficiencyd. Adverse effects:

i. Placebo-like incidence of adverse effects (upper respiratory, headache, urinary tract infections)ii. Rare: Pancreatitis, skin reactions

e. Contraindications:i. History of pancreatitisii. Diabetic ketoacidosisiii. Type 1 DM

f. Advantagesi. No hypoglycemia as monotherapyii. Weight neutraliii. Placebo-like adverse effect profileiv. Potential B-cell–sparing effect?

g. Disadvantagesi. Modest A1c loweringii. Expensive

9. Bile acid sequestrant – Colesevelam (Welchol)a. Mechanism of action: Farnesoid X receptor (FXR) antagonist. Bile acids activate the FXR, which

leads to increased expression of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme necessary for hepatic gluconeogenesis. Colesevelam inhibits bile acid reabsorption, thus preventing FXR activation and up-regulation of PEPCK, leading to decreased hepatic glucose production.

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b. Efficacy:i. Hemoglobin A1c lowering of 0.4%–0.6%ii. Mixed blood glucose–lowering effectiii. Low-density lipoprotein cholesterol reduction of 15%–18%

c. Dose:i. 625-mg tablets, 3 tablets twice daily or 6 tablets every day with mealsii. Suspension 3.75 g/packet, 1 every day with largest meal

d. Adverse effects:i. Constipation/dyspepsiaii. Potential TG increase

e. Contraindications:i. Bowel obstructionii. Triglycerides greater than 500 mg/dLiii. History of hypertriglyceridemia-induced pancreatitis

f. Advantagesi. No hypoglycemia as monotherapyii. Low-density lipoprotein cholesterol lowering of 15%–18%

g. Disadvantagesi. Modest A1c efficacyii. High pill burdeniii. May raise TGiv. Potential for drug interactions (levothyroxine, ezetimibe, phenytoin)

10. Bromocriptine (Cycloset)a. Mechanism of action:

i. Dopamine receptor agonistii. Glucose-lowering mechanism is unknown but improves glucose and energy metabolism and

does NOT increase plasma insulin concentration; acts to reset aberrant central neurometabolic control of peripheral metabolism toward normal in patients with diabetes, resulting in a reduction in insulin resistance; improves glucose and energy metabolism through activation of central nervous system dopaminergic pathways responsible for metabolic control

b. Efficacy:i. Hemoglobin A1c lowering of 0.4%–0.6%ii. Modestly reduces postprandial blood glucose; even less effect on FBG

c. Dose: A 0.8-mg tablet each morning (within 2 hours of waking) with food; titrate by 0.8 mg/week to mean daily dose of 4.8 mg (6 tablets) each morning

d. Adverse effects:i. Nausea/vomitingii. Astheniaiii. Constipationiv. Dizzinessv. Somnolence

e. Contraindications:i. Hypersensitivity to ergot derivative or dopamineii. Lactationiii. Syncopal migraines

f. Advantages: Unique mechanism of action

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g. Disadvantagesi. Modest efficacyii. Adverse effectsiii. Cost

11. Combination of oral diabetes medicationsa. Actoplus Met—Pioglitazone and metforminb. Avandamet—Rosiglitazone and metforminc. Avandaryl—Rosiglitazone and glimepirided. Duetact—Pioglitazone and glimepiridee. Glucovance—Glyburide and metforminf. Janumet—Sitagliptin and metformin

Janumet XR—Sitagliptin and metformin XRg. Jentadueto—Linagliptin and metforminh. Kombiglyze XR—Saxagliptin and metformin XRi. Metaglip—Metformin and glipizidej. Prandimet—Repaglinide and metformin

Patient Case2. A 65-year-old patient with type 2 DM, diagnosed 3 years ago, is currently treated with sitagliptin. He notes

that his FBG is too high (180–200 mg/dL). He has a seafood allergy, no known drug allergies, and normal organ function. Which one of the following medication recommendations is best?A. Acarbose.B. Bromocriptine.C. Metformin.D. Repaglinide.

12. Amylin analog – pramlintide (Symlin)a. Mechanism of action: Synthetic analog of human amylin, causes

i. A glucose-dependent inhibition of glucagon secretionii. A reduced rate of gastric emptyingiii. Increased satiety

b. Efficacy (indicated for patients receiving mealtime insulin):i. Hemoglobin A1c lowering of 0.5%–0.7%ii. Primarily lowers postprandial glucose levels

c. Dose:i. Type 1 DM: Initiate at 15 mcg subcutaneously with meals daily, increase by 15 mcg per dose

every 3–7 days based on tolerability and response; maximum of 60 mcg with meals (mealtime insulin dose must be reduced by 50% at initiation of pramlintide)

ii. Type 2 DM: Initiate at 60 mcg with meals, increase to 120 mcg with meals in 3–7 days (mealtime insulin dose must be reduced by 50% at initiation of pramlintide)

d. Adverse effects:i. Nauseaii. Vomitingiii. Hypoglycemia with insulin (mealtime insulin dose must be reduced by 50% at initiation of

pramlintide)

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e. Contraindications:i. Gastroparesisii. Hypoglycemic unawarenessiii. A1c greater than 9%iv. Patients unwilling to self-monitor blood glucose

f. Advantages:i. Use is associated with weight loss.ii. Primarily targets postprandial sugars

g. Disadvantagesi. Requires three additional injections per day (it cannot be mixed with insulin)ii. May reduce the rate and extent of absorption of drugs that require rapid absorption such as

pain relievers, antibiotics, and oral contraceptives; separate administration by at least 1 houriii. Gastrointestinal adverse effects

13. Incretin analogsa. Mechanism of action: Synthetic analog of human glucagon-like peptide-1 results in

supraphysiologic (pharmacologic) incretin levels, causing 1) a glucose-dependent increase in insulin secretion, 2) a glucose-dependent inhibition of glucagon secretion, 3) reduced gastric emptying, and 4) increased satiety.

b. Efficacy:i. Hemoglobin A1c lowering of 0.6%–1.5%ii. Primarily a postprandial glucose reduction with exenatideiii. Less postprandial and greater fasting glucose reduction with liraglutide

c. Dose:i. Exenatide (Byetta): 5 mcg subcutaneously 2 times/day before meals (thigh, abdomen, or

upper arm), 1–60 minutes before morning and evening meals, increase to 10 mcg before breakfast and dinner after 4 weeks if tolerated

ii. Liraglutide (Victoza): 0.6 mg subcutaneously once daily (independent of meals; inject into thigh, abdomen, or upper arm); increase by weekly intervals to 1.2 mg subcutaneously every day; then 1.8 mg subcutaneously every day if needed

iii. Exenatide extended release (Bydureon): 2 mg subcutaneously once weekly (independent of meals; inject into thigh, abdomen, or upper arm)

d. Adverse effects:i. Nauseaii. Vomitingiii. Diarrheaiv. Headachev. Rare: Pancreatitis/renal dysfunction

e. Contraindications:i. Gastroparesisii. Pancreatitisiii. For exenatide only: CrCl less than 30 mL/minuteiv. For liraglutide and exenatide extended release only: Personal or family history of medullary

thyroid carcinoma; in patients with multiple endocrine neoplasia syndrome type 2f. Advantages

i. Use is associated with weight loss.ii. Convenient dosingiii. No priming required after initial doseiv. Beta cell–sparing effect?

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g. Disadvantagesi. May reduce rate and extent of absorption of drugs that require rapid absorption such as pain

relievers, antibiotics, and oral contraceptives; separate administration by at least 1 hourii. Requires subcutaneous injection once or twice dailyiii. Cost

Patient Case3. A patient with type 2 DM receiving premeal insulin is interested in a “new” drug that he heard would allow

him to significantly decrease his premeal insulin doses and allow better glycemic control. Which one of the following is the best choice to allow this patient to decrease his premeal insulin doses and allow better glycemic control ?A. Liraglutide.B. Metformin.C. Pramlintide.D. Bromocriptine.

14. Considerations for initiation of drug therapy in type 2 DMa. Baseline A1c/blood glucose levels; sugars of 250 mg/dL or higher typically require insulin for

initial therapyb. Organ function: Certain diabetes medications must be avoided or doses adjusted on the basis of the

individual patient’s renal and hepatic function.c. Contraindications to therapy: Know when NOT to use a particular therapy.d. Duration of DM: Less B-cell function as disease progresses; may limit utility of some drug choices

(secretagogues)e. Self-monitoring of blood glucose: A patient who is going to start insulin must monitor his or her

blood glucose to maximize its potential (for dose adjustment) as well as to reduce the risk of hypoglycemia.

f. Hypoglycemic unawareness: Avoid secretagogue use or insulin therapy if possible in patients with neuroglycopenia; frequent glucose monitoring is imperative for these patients; A1c targets will be higher for these patients (e.g., 8%).

g. Baseline weight: Weight gain exacerbates control of glucose, blood pressure (BP), and lipids. Encourage medications that are weight neutral or associated with weight loss if possible.

h. Route of administration: Some patients will refuse parenteral therapy.i. Cost: High medication costs and/or co-pays may discourage medication use by patients.

Sulfonylureas and metformin are very inexpensive (e.g., $4/month).j. Start with single or combination drug therapy? Depending on baseline A1c, which drug caused the

adverse effect, etc.15. The ADA/European Association for the Study of Diabetes algorithm for management of type 2 DM

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At diagnosis:

Lifestyle+

Metformin

Lifestyle + Metformin+

Basal insulin

Tier 1: Well validated core therapies

Tier 2: Less well validated therapies

STEP 1 STEP 2 STEP 3


Intensive insulin


Sulfonylureaa


Pioglitazone

No hypoglycaemiaOedema/CHFBone loss


GLP -1 agonist b

No hypoglycaemiaWeight lossNausea/vomiting


Pioglitazone+

Sulfonylurea a


Basal insulin

Figure 1. The American Diabetes Association/European Association for the Study of Diabetes algorithm for management of type 2 DM.CHF = chronic heart failure; GLP-1 = glucagon-like peptide-1.Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association, European Association for Study of Diabetes. Diabetes Care 2009;32:193–203.

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Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

AACE/ACE Diabetes Algorithm For Glycemic Control A1C Goal≤ 6.5%*

L I F E S T Y L E M O D I F I C AT I O N

Figure 2. AACE/ACE Diabetes Algorithm for Glycemic Control. AGIs = α-glucosidase inhibitors; DPP-4 = dipeptidyl-peptidase-4; glinide = meglitinide; GLP-1 = glucagonlike peptide-1; Met = metformin; SU = sulfonylurea; TZD = thiazolidinedione.Reprinted with permission from the American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control. Available at www.aace.com/pub/pdf/GlycemicControlAlgorithmPPT.pdf. Reprinted with permission from the American Association of Clinical Endocrinologists.

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Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

AACE/ACE Diabetes Algorithm For Glycemic Control A1C Goal≤ 6.5%*

L I F E S T Y L E M O D I F I C AT I O N

Patient Case4. J.L. is a 48-year-old obese white woman with type 2 DM, currently receiving metformin 1 g twice daily,

whose postprandial blood glucose is higher than desired, and her most recent A1c is 7.5%. Which one of the following best represents how J.L.’s diabetes regimen should be changed?A. Increase the metformin dose to 850 mg 3 times/day.B. Substitute metformin with a sulfonylurea.C. Add a bedtime dose of NPH insulin.D. Add sitagliptin 100 mg orally every day.

16. Insulina. Comparison of human insulins

Table 2. Comparison of Human Insulins Category Insulin Onset of Insulin Action Peak Effect Duration of ActionRapid acting Lispro insulin

Aspart insulin Glulisine insulina

5–15 minutes 1–2 hours 3–5 hours

Short acting Human regular 30–60 minutes 2–4 hours 6–8 hoursIntermediate Human NPH 1–2 hours 6–12 hours 10–16 hoursLong acting Detemir insulina Insulin glarginea 3–4 hours

4–6 hoursPeaklessPeakless

6–24 hours~24 hours

aInsulin analog.NPH = neutral protamine Hagedorn (insulin).

b. Basal insulin (detemir, glargine, NPH)i. Decreases fasting glucose productionii. Requires consistent (constant) insulin levelsiii. Approximates 50% of daily insulin needsiv. Equivalent doses

(a) 60 units of NPH once daily equals 60 units of glargine once daily or 60 units of detemir once daily.

(b) 30 units of NPH 2 times/day equals 48 units of glargine once daily or 60 units of detemir once daily.

c. Bolus insulin (regular, aspart, glulisine, lispro)i. Limits postprandial hyperglycemiaii. Requires immediate insulin peakiii. Each meal requires 10%–20% of daily insulin requirements.iv. Glucose monitoring and insulin dosing

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Table 3. Individual Insulins and Their Appropriate Blood Glucose Targets

Target Blood Glucose Target InsulinFasting (prebreakfast) Bedtime or predinner NPH, detemir, glarginePrelunch Prebreakfast regular, aspart, glulisine, lisproPredinner Prebreakfast NPH, detemir; prelunch regular, aspart, glulisine, lisproBedtime Predinner regular, aspart, glulisine, lispro

NPH = neutral protamine Hagedorn.

d. Initial dosing of insulini. Type 2 DM—Initiating insulin therapy (fix the fasting first!)

(a) Continue oral agent(s) at same dosage (may eventually reduce or discontinue, especially secretagogue).

(b) Add single bedtime insulin dose (glargine, detemir, or NPH, 10–20 units or 0.1–0.2 unit/kg).

(c) Adjust dose according to FBG (treat to target) (e.g., 80–100 mg/dL).(1) Increase the insulin dose every 3–4 days as needed.(2) Increase 2 units if FBG is 100–140 mg/dL.(3) Increase 4 units if FBG is 141–180 mg/dL.(4) Increase 6 units if FBG is 181–220 mg/dL.(5) Increase 8 units if FBG is greater than 200 mg/dL.

(d) Cut back to previous dose immediately (next dose) if FPG is ever below 80 mg/dL.

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NPH = neutral protamine Hagedorn.

Figure 3. Initiation and adjustment of insulin in type 2 DM.From Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association, European Association for Study of Diabetes. Diabetes Care 2009;32:193–203.

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Patient Case5. C.D. is a 19-year-old white woman, just given a diagnosis of type 1 DM. She weighs 80 kg and has normal

renal function (serum creatinine 0.6 mg/dL). Which one of the following choices represents the most ap-propriate empiric basal insulin and dose for C.D.?A. Glargine 10 units at bedtime.B. Glargine 20 units at bedtime.C. NPH insulin 20 units at bedtime.D. NPH 40 units at bedtime.

ii. Type 1 DM: Initiating multiple daily insulin injection therapy with insulin analogs(a) Calculate daily dose (0.5 unit of insulin per kilogram per day). Give 50% as basal insulin.(b) Give 50% as bolus insulin. Split into three mealtime doses. Example: 80-kg patient

starting multiple daily injection therapy: 0.5 unit/kg = 40 units of insulin/day; half as basal, half as bolus, with:(1) Glargine (or detemir) 20 units every day(2) Aspart (or glulisine, lispro) 6 units prebreakfast(3) Aspart (or glulisine, lispro) 7 units prelunch(4) Aspart (or glulisine, lispro) 7 units predinner(5) Titrate insulin doses to blood glucose.

(c) Correctional insulin dosing—Meant to correct for premeal glycemic excursions: Premeal algorithm: Rapid-acting insulin (the rule of 1800): 1800/current total daily insulin dose = mg/dL change/1 unit (e.g., 40 units/day: 1800/40 = 45 mg/dL [insulin sensitivity]). Titrate to the following algorithm:Less than 80 mg/dL Subtract 1 unit.80–125 mg/dL Usual premeal dose (fixed or based on CHO

[carbohydrate] intake)126–170 mg/dL Add 1 unit.171–215 mg/dL Add 2 units.215–260 mg/dL Add 3 units.

e. Regular insulin (the rule of 1500): 1500/current total daily insulin dose = mg/dL change/1 unit (e.g., 50 units/day: 1500/50 = 30 mg/dL [insulin sensitivity]). Titrate to the following algorithm:

Less than 80 mg/dL Subtract 1 unit.80–110 mg/dL Usual dose111–140 mg/dL Add 1 unit.141–170 mg/dL Add 2 units.171–200 mg/dL Add 3 units.

f. Establishing an insulin-to-carbohydrate ratioInsulin-to-carbohydrate ratio (the rule of 500)—This requires extensive patient education on counting carbohydrates and may be used to estimate the early use of rapid-acting insulins at mealtime to prospectively cover what is to be ingested. 500/daily insulin dose = insulin-to-carbohydrate ratio (e.g., 50 units/day: 500/50 = 10). Insulin-to-carbohydrate ratio = 1 unit for 10 g of carbohydrates.

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Patient CaseB.L. is a 70-year-old patient with type 2 DM, diagnosed 28 years ago. His indirect measure of endogenous in-sulin secretion (C-peptide level) is undetectable, and he receives a basal/bolus insulin regimen of glargine and lispro insulins. His insulin requirements total 100 units of insulin per day.

6. Which one of the following choices best approximates B.L.’s insulin sensitivity?A. 15 mg/dL.B. 16 mg/dL.C. 17 mg/dL.D. 18 mg/dL.

7. Which one of the following choices best approximates B.L.’s insulin-to-carbohydrate ratio?A. 3.B. 4.C. 5.D. 6.

8. B.L.’s presupper reading today is 184 mg/dL (goal of 130 mg/dL), and he plans to eat 60 g of carbohydrates at dinner. Which one of the following choices best approximates B.L.’s predinner lispro insulin dose?A. 15 units.B. 16 units.C. 17 units.D. 18 units.

g. Mixed insulins1. Humulin 70/30: 70% NPH, 30% regular2. Humalog Mix 75/25: 75% lispro protamine, 25% lispro3. Humalog Mix 50/50: 50% lispro protamine, 50% lispro4. Novolin 70/30: 70% NPH, 30% regular5. NovoLog Mix 70/30: 70% aspart protamine, 30% aspart

h. Insulin delivery devices (pens, pumps, etc.). Before health care professionals can recommend a medication delivery device, it is critical they understand not only the medication in the device but also the various features and benefits of the different devices available and how those affect the patient. Knowledge and competence of insulin pens and pumps, glucagon-like peptide-1 and amylin analog devices, glucose monitoring systems, site care, device storage and priming, the injection process, proper use of pens and syringes, needle length, skinfolds, site rotation, and proper device disposal are important for maximal patient benefit. For example, pen-type insulin delivery devices allow more accurate dosing, faster and easier setting of dose, and increased patient acceptance and adherence compared with insulin and syringe use, but they are more expensive.

17. Bariatric surgerya. Laparoscopic Roux-en-Y gastric bypassb. Laparoscopic gastric banding (Campos GM, Rabl C, Roll GR et al. Better weight loss, resolution

of diabetes, and quality of life for laparoscopic gastric bypass vs. banding: results of a 2-cohort pair-matched study. Arch Surg 2011;146:149–55)

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K. Point-of-Care Testing: Point-of-care testing can be used by clinicians to screen for diabetes (using glucose monitors and A1c tests), adjust diabetes medication regimens (A1c tests), identify and improve the care of patients with diabetes with hyperlipidemia (cholesterol test), and screen for and treat diabetic nephropathy/chronic kidney disease (urine microalbumin determination). In addition, point-of-care testing (blood glucose and A1c) allows patients the opportunity to take a more active role in their own disease management.

L. New-Drug Treatment Requirements. Approval of all new diabetes drugs is now contingent on proof of CV safety. New FDA regulations went into effect in 2008 in the wake of the rosiglitazone CV safety issues. The regulations require:1. Approval of diabetes drugs only with the exclusion of a 30% relative increase in CV events compared

with placebo or an active comparator, or of an 80% relative excess of events with a postmarketing study to formally evaluate the risk.

2. Data on patients with advanced diabetes, elderly patients, and those with some degree of renal impairment are included in the regulatory submission—groups typically excluded from pivotal trials.

3. At least 2 years of CV safety data, to include major adverse CV events as an end point with independent adjudication of events

M. Diabetes Complications1. Acute complications

a. Hypoglycemia: Signs/symptoms of hypoglycemiai. Blood glucose usually below normal (less than 60 mg/dL)ii. Patient may:

(a) Feel tremulous(b) Feel nervous/anxious(c) Be diaphoretic(d) Be tachycardic(e) Feel hungry(f) Experience a headache

iii. Provider/family member may notice:(a) Irritability(b) Confusion(c) Sleepiness

iv. Treatment(a) If conscious, give 15 g of CHO (4 lifesavers, 4 teaspoonsful of sugar, a half can of soda

or juice, glucose gel)(b) Give long-acting source of CHO (e.g., one-half of a sandwich).(c) Recheck blood glucose in 15 minutes, and repeat above if reading remains below 70 mg/

dL or patient remains symptomatic.(d) If unconscious, inject glucagon intramuscularly.(e) Look for causes; adjust insulin doses if repeated hypoglycemia

b. Diabetic ketoacidosis—A low-insulin, high-glucagon statec. Hyperglycemic hyperosmolar stated. Sick-day rules for patients receiving insulin

i. Never stop insulin: Continue basal insulin at normal dose and cover with quick-acting insulin (discontinue scheduled doses of quick-acting insulin if the patient is not eating, but use every 4–6 hours to keep blood sugar below 250 mg/dL).

ii. Hydration: 8–12 oz of fluid (with calories) per hour (e.g., sports drink)iii. Self-monitoring of blood glucose: Check every 1–2 hours if sugars are more than 250 mg/dL.

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iv. Check for ketones: Check urine every 4 hours when blood glucose is greater than 250 mg/dL.v. Call a physician as soon as possible if vomiting occurs with blood glucose greater than 500 mg/

dL or if moderate-large amounts of urine ketones are present with a blood glucose greater than 250 mg/dL.

2. Chronic complicationsa. Microvascular

i. Retinopathy—Leading cause of adult-onset blindness in the United States; a comprehensive eye examination by an ophthalmologist or optometrist should be performed annually

ii. Nephropathy—Often a progression from microalbuminuria to macroalbuminuria to increases in serum creatinine to end-stage renal disease; nephropathy occurs in 20%–40% of patients with diabetes and represents the No. 1 cause of end-stage renal disease in this country. Measure serum creatinine and urine for albuminuria at least annually. Treat microalbuminuria (albuminuria in the range of 30–299 mg/24 hours or 30–299 mcg/mg of creatinine) or macroalbuminuria (albuminuria 300 mg/24 hours or greater or 300 mcg/mg or greater of creatinine) with ACEI or angiotensin receptor blocker (ARB) therapy.

iii. Trials(a) DCCT Diabetes Control and Complications Trial)(b) UKPDS

b. Macrovascular (diabetes is a coronary disease risk equivalent!). Diabetes mellitus is the sixth leading cause of death in the United States.i. Coronary artery diseaseii. Cerebrovascular diseaseiii. Peripheral arterial disease (ulcers, Charcot joints, amputation)—Leading cause of

nontraumatic lower limb amputations in the country. All patients require daily foot inspections, assessment of foot pulses, and testing for loss of protective sensation.

iv. Trials(a) Action to Control Cardiovascular Risk in Diabetes(b) Action in Diabetes and Vascular Disease(c) Veterans Affairs Diabetes Trial(d) Take-home point – An aggressive A1c goal in patients with long-standing diabetes may be

more harmful than helpful.c. Neurologic

i. Peripheral neuropathy—All patients should be screened for distal symmetric polyneuropathy at diagnosis and at least annually thereafter using pinprick sensation, tuning fork, and 10-g monofilament pressure sensation tests.

ii. Autonomic neuropathies(a) Gastroparesis(b) Erectile dysfunction(c) Urinary retention(d) Diabetic diarrhea(e) Cardiovascular autonomic neuropathy (e.g., orthostatic hypotension, resting tachycardia)(f) Hypoglycemic unawareness (neuroglycopenia)

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N. Monitoring—Prevention and Management of Diabetes Complications. Attainment of appropriate A1c with self-monitoring of blood glucose, together with appropriate and regular eye, foot, kidney, nerve, and CV examinations, aims at reducing the burden of diabetes-related complications1. Mind your ABC’s

a. A’si. Hemoglobin A1c

ii. Antiplatelet therapy (aspirin, 75–162 mg/day)—See 2e. Antiplatelet Agents below.b. B’s

i. Blood pressure control (ACEI/ARB)—Goal BP less than 130/80 mm Hgii. See 2b. below.

c. C’si. Cholesterol control (statin)—Goal LDL-C less than 100 mg/dL (optional less than 70 mg/

dL), goal HDL-C greater than 40 mg/dL in men, greater than 50 mg/dL in women; goal TG less than 150 mg/dL. Heart Protection Study showed CV benefit of a 30%–40% reduction in LDL-C even in patients with baseline LDL-C below 100 mg/dL.

ii. Cessation of cigarette smoking2. Recommendations for primary prevention of CVD in people with diabetes (AHA and ADA.

Circulation 2007;115:114–26 and ADA Standards of Care—2011)a. Lifestyle management

i. Weight control(a) Weight reduction in obese individuals will reduce all the CVD risk factors associated

with type 2 DM and will improve hyperglycemia.(b) Moderate weight loss versus ideal body weight(c) A 5%–10% weight loss is associated with profound health benefits.(d) Weight maintenance versus weight gain(e) Diet versus surgery

ii. Medical nutrition therapy(a) Total energy intake to achieve body-weight goals(b) Total dietary fat intake: 25%–35% of total calories; mainly monounsaturated or

polyunsaturated fat(c) Ample intake of dietary fiber (14 g/1000 calories)(d) Alcohol limited: 1 drink for women, 2 drinks/day for men(e) Lipid goal attainment

(1) Saturated fats: 7% of energy intake(2) Dietary cholesterol intake: 200 mg/day(3) Intake of trans-unsaturated fatty acids: 1% of energy intake

(f) Blood pressure attainment—A reduction in sodium intake: 1200–2300 mg/day(g) Physical activity

(1) At least 150 minutes of moderate-intensity aerobic physical activity or 90 minutes of vigorous aerobic exercise per week

(2) The physical activity should be distributed over at least 3 days/week, with no more than 2 consecutive days without physical activity

(3) For long-term maintenance of major weight loss, a larger amount of exercise (7 hours of moderate or vigorous aerobic physical activity per week) may be helpful.

b. Blood pressurei. Blood pressure should be measured at every routine visit.ii. Patients with diabetes goals: Systolic BP less than 130 mm Hg and diastolic BP less than 80

mm Hg

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iii. Patients with pre-HTN should initiate lifestyle modifications alone for a maximum of 3 months. If targets are not achieved, treatment with pharmacologic agents should be initiated.

iv. All patients with DM and HTN should be treated with a regimen that includes either an ACEI or an ARB because of their well-documented renoprotective effects.

v. Multidrug therapy is generally required to achieve BP targets.vi. In elderly patients with HTN, BP should be lowered gradually to avoid complications; include

orthostatic measurement of BP.c. Lipids

i. Adults—Measure lipids at least annually.ii. Lifestyle modificationsiii. Older than 40 years, without overt CVD, but with one or more major CVD risk factors, the

primary goal is an LDL-C concentration less than 100 mg/dL, a reduction of at least 30%–40% of LDL-C concentrations.

iv. Younger than 40 years, without overt CVD, but estimated to be at increased risk of CVD, the LDL-C goal is less than 100 mg/dL; LDL-lowering drugs should be considered if lifestyle changes do not achieve the goal.

v. The ADA and the American Heart Association suggest different approaches to the management of HDL- and TG-associated CVD risk.(a) American Heart Association: If TG concentrations are 200–499 mg/dL, a non–HDL-C

(TC minus HDL-C) goal of 130 mg/dL is a secondary target. If TG concentrations are more than 500 mg/dL, therapeutic options include fibrate or niacin before LDL-lowering therapy and treatment of LDL-C to goal after TG-lowering therapy. A non–HDL-C concentration less than 130 mg/dL should be achieved if possible.

(b) ADA: TG concentrations less than 150 mg/dL and HDL-C greater than 40 mg/dL (women: greater than 50 mg/dL). Combination therapy of LDL-lowering drugs (e.g., statins) and fibrates or niacin may be necessary to achieve lipid targets, but this has not been extensively evaluated in outcomes studies for either CVD event reduction or safety.

d. Tobaccoi. All patients with diabetes should be asked about tobacco use status at every visit.ii. Every tobacco user should be advised to quit.iii. The tobacco user’s willingness to quit should be assessed.iv. The patient can be assisted by counseling and by developing a plan to quit.v. Follow-up, referral to special programs, or pharmacotherapy (including nicotine replacement

and bupropion) should be incorporated as needed.e. Antiplatelet agents

i. Aspirin therapy (75–162 mg/day) should be recommended as a primary prevention strategy in those with diabetes at increased CV risk (10-year risk of 10% or greater), including men 50 years old or women 60 years old with one additional risk factor (family history of CVD, HTN, smoking, dyslipidemia, or albuminuria).

ii. People with aspirin allergy, bleeding tendency, existing anticoagulant therapy, recent GI bleeding, and clinically active hepatic disease are not candidates for aspirin therapy.

iii. Other antiplatelet agents may be a reasonable alternative for patients with high risk.iv. Aspirin therapy should not be recommended for patients younger than 21 years because of the

increased risk of Reye syndrome associated with aspirin use in this population.f. Immunizations

i. Influenza – Annuallyii. Pneumococcal – One lifetime dose unless received before age 65 (second dose would be

given after age 65, a minimum of 5 years after the first dose)

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O. My Diabetes Checklist1. Hemoglobin A1c of 7% or less (6.5%) – Individualize2. Blood pressure 130/80 mm Hg or less (ACEI/ARB)3. Low-density lipoprotein cholesterol of 100 (70) mg/dL or less (statin)4. Daily aspirin use for vascular protection5. Smoking cessation6. Immunizations (influenza, pneumococcal)7. Urinalysis8. Daily feet inspection9. Annual dilated eye examinations10. Realistic exercise program11. Weight loss (5%–10%)12. Dental examinations (periodontal disease)

P. Diabetes Credentialing1. Certified Diabetes Educator (CDE)—Title given to a health professional with specialized training in

diabetes treatment and education. To qualify as a CDE, a health professional must have completed at least 2000 hours of hands-on diabetes education and must pass an examination given by the National Certification Board of Diabetes Educators. The examination covers a wide range of current knowledge in diabetes treatment and education.

2. Board Certified in Advanced Diabetes Management (BC-ADM)—The result of an initiative of the American Association of Diabetes Educators and the ADA to recognize and serve as a means of verifying clinical care skills among advanced practitioners in diabetes care. The American Nurses Credentialing Center, the Commission on Dietetic Registration of the American Dietetic Association, and the American Pharmaceutical Association have all supported the concept of this relatively new credential (first offered in 2002), and they were involved in its planning and development. Available for nurses, dietitians, and pharmacists who have advanced degrees, it is different from the CDE credential because it focuses on advanced clinical management of diabetes. Advanced-practice dietitians, pharmacists, and nurses seeking certification take different versions of the examination (the examination is designed specifically for one’s own profession), and each examination covers the domains of clinical practice, collaboration, research, patient and professional diabetes education, and public and community health.

Q. Practice ManagementAbout $1 in $6 of the gross domestic product is spent on health care, yet only half of eligible patients receive the recommended preventive, chronic disease, and acute care services. Pharmacists can help bridge the gap in the provision of health care as they continue to involve themselves in the prevention of disease, recommend and monitor medication therapy to achieve desired clinical effects, and reduce drug misadventuring. Nowhere is this truer than in the medical management of patients with diabetes, where pharmacists have shown the ability to provide high-quality, cost-effective, direct patient care. For example, the Asheville Project assessed the 5-year clinical and economic outcomes of pharmaceutical care services provided by community pharmacists to patients with DM. The results of this partnership showed that patients improved their A1c values and used fewer sick days while lowering their employers’ total health care costs. Many states also have provisions in place that allow pharmacist participation in disease and drug management programs. Collaborative practice agreements are arrangements between specific pharmacists and physicians that allow pharmacists to directly initiate and modify drug therapy regimens for patients.

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R. Patient Education Resources1. American Diabetes Association (www.diabetes.org/)2. CDC – Diabetes & Me (www.cdc.gov/diabetes/consumer/)3. National Diabetes Information Clearinghouse (http://diabetes.niddk.nih.gov/)4. National Diabetes Education Program (http://ndep.nih.gov/)5. American Association of Diabetes Educators (www.diabeteseducator.org/DiabetesEducation/Patient_

Resources/AADE_NDEP_Resources.html)6. Life for Your Diabetes Life (www.dlife.com)7. The Diabetes Library (http://diabetes.boomja.com/Diabetes-Patient-Education-Resources-111.html)8. California Diabetes Program (www.caldiabetes.org/content.cfm?CategoriesID=75)9. Texas Department of State Health Services (www.dshs.state.tx.us/diabetes/patient.shtm)10. Merck Medicus Patient Information (www.merckmedicus.com/pp/us/hcp/templates/tier2/patientEdu.

jsp?tcode=H17V8&WT.mc_id=H17V8&WT.srch=1)

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REFEREnCES

1. Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes melli-tus: the Diabetes Control and Complications Trial. N Engl J Med 1993;329:978–86.

2. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with NIDDM: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103–17.

3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonyl-ureas or insulin compared with conventional treat-ment and risk of complication in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53.

4. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metfor-min on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65. UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovas-cular and microvascular complications in type 2 diabetes. BMJ 1998;317:703–13.

5. Diabetes Prevention Program Research Group. Reduction in incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.

6. Diabetes Control and Complications Trial/Epide-miology of Diabetes Interventions and Complica-tions Research Group. Intensive diabetes therapy and carotid intima–media thickness in type 1 dia-betes. N Engl J Med 2003;348:2294–303.

7. Cranor CW, Bunting BA, Christensen DB. The Asheville Project: long-term clinical and economic outcomes of a community pharmacy diabetes care program. J Am Pharm Assoc 2003;43:173–84.

8. Sjostrom L, Lindroos AK, Peltonen M, et al. Life-style, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–93.

9. Pontiroli AE, Folli F, Paganelli M, et al. Laparo-scopic gastric banding prevents type 2 diabetes and arterial hypertension and induces their remission in morbid obesity: a 4-year case-controlled study. Diabetes Care 2005;28:2703–9.

10. Diabetes Prevention Program Research Group. Impact of intensive lifestyle and metformin ther-apy on cardiovascular disease risk factors in the Diabetes Prevention Program. Diabetes Care 2005;28:888–94.

11. Kahn R, Buse J, Ferrannini E, Stern M; American Diabetes Association; European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the Euro-pean Association for the Study of Diabetes. Diabe-tes Care 2005;28:2289–304.

12. Nathan DM, Cleary PA, Backlund JY, et al; Dia-betes Control and Complications Trial/Epidemiol-ogy of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53.

13. The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequen-cy of diabetes in patients with impaired glucose tol-erance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096–105.

14. Narrative Review. A rational approach to starting insulin. Ann Intern Med 2006;145:125–34.

15. Stettler C, Allemann S, Jüni P, et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am Heart J 2006;152:27–38.

16. Kahn SE, Haffner SM, Heise MA, et al; for the ADOPT Study Group. Glycemic durability of rosi-glitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427–43.

17. Rodbard HW, Blonde L, Braithwaite SS, et al; AACE Diabetes Mellitus Clinical Practice Guide-lines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007;13(Suppl 1):1–68.

18. Bolen S, Feldman L, Vassy J, et al. Systematic re-view: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann In-tern Med 2007;147:386–9.

Diabetes Mellitus


1-165

19. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes (treat to new targets in type 2 diabetes) year 1. N Engl J Med 2007;357:1716–30.

20. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular disease in people with diabetes mellitus. A scientific statement from the American Heart Association and the American Di-abetes Association. Circulation 2007;115:114–26.

21. Gaede P, Lund-Andersen H, Parving HH, Ped-ersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580–91.

22. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA 2008;299:316–23.

23. Nathan DM, Buse JB, Davidson MB, et al. Man-agement of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjust-ment of therapy: update regarding the thiazolidin-ediones. Diabetologia 2008;51:8–11.

24. Nathan DM, Buse JB, Davidson MB, et al. Man-agement of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjust-ment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006;29:1963–72.

25. 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;358:2545–59.

26. ADVANCE Collaborative Group; Patel A, Mac-Mahon S, Chalmers J, et al. Intensive blood glu-cose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–72.

27. Abraira C, Duckworth WC, Moritz T; for the VADT Group. Glycaemic separation and risk factor con-trol in the Veterans Affairs Diabetes Trial: an in-terim report. Diabetes Obes Metab 2009;11:150–6.

28. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular com-plications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–39.

29. Nathan DM, Buse JB, Davidson MB, et al; Ameri-can Diabetes Association, European Association for the Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consen-sus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Asso-ciation for the Study of Diabetes. Diabetes Care 2009;32:193–203.

30. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinol-ogy consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control [published cor-rection appears in Endocr Pract 2009;15:768–70]. Endocr Pract 2009;15:540–59.

31. Woo V. Important differences: Canadian Diabetes Association 2008 clinical practice guidelines and the consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009;52:552–3.

32. Kelly TN, Bazzano LA, Fonseca VA, et al. Sys-tematic review: glucose control and cardiovas-cular disease in type 2 diabetes. Ann Intern Med 2009;151:394–403.

33. Kulasa KM, Henry RR. Pharmacotherapy of hyper-glycemia. Expert Opin Pharmacother 2009;10:15–32.

34. Skyler JS, Bergenstal R, Bonow RO, et al. Inten-sive glycemic control and the prevention of car-diovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol 2009;53:298–304.

35. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(Suppl 1):S11–S61.

36. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinolo-gists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011;17(Suppl 2):1–53.

37. Pozzilli P, Leslie RD, Chan J, et al. An A1C and ABCD of glycaemia management in type 2 diabe-tes: a physician’s personalized approach. Diabetes Metab Res Rev 2010;26:239–44.

Diabetes Mellitus


1-166

38. Bergenstal RM, Bailey CJ, Kendall DM. Type 2 diabetes: assessing the relative risks and ben-efits of glucose-lowering medications. Am J Med 2010;123:374–82.

39. Brown A, Reynolds LR, Bruemmer D. Intensive glycemic control and cardiovascular disease: an update. Nat Rev Cardiol 2010;7:369–75.

40. Chisholm-Burns MA, Graff Zivin JS, Lee JK, et al. Economic effects of pharmacists on health out-comes in the United States: a systematic review. Am J Health Syst Pharm 2010;67:1624–34.

41. Colberg SR, Albright AL, Blissmer BJ, et al. American College of Sports Medicine; Ameri-can Diabetes Association. Med Sci Sports Exerc 2010;42:2282–303.

42. Campos GM, Rabl C, Roll GR, et al. Better weight loss, resolution of diabetes, and quality of life for laparoscopic gastric bypass vs. banding: re-sults of a 2-cohort pair-matched study. Arch Surg 2011;146:149–55.

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AnSwERS AnD ExPLAnATIOnS TO PATIEnT CASES

1. Answer: BThe patient has an FBG value consistent with diabetes (greater than 125 mg/dL). However, because she is as-ymptomatic, the diagnosis of diabetes is made on the basis of two diabetes diagnostic tests completed on sep-arate days, with the results of the second test in the dia-betes range (FPG of 126 mg/dL or more, 2-hour OGTT of 200 mg/dL or more, symptomatic with casual blood glucose of 200 mg/dL or more, and A1c of 6.5% or more) confirming the diagnosis.

2. Answer: COf the listed answers, only metformin primarily lowers FBG levels. Acarbose and repaglinide primarily lower postprandial blood glucose, whereas bromocriptine has a mixed effect. Metformin is also the recommended ini-tial drug of choice in the current ADA treatment guide-lines.

3. Answer: COf the listed choices, only Symlin is approved by the FDA for use in patients taking premeal insulin. To lower the risk of hypoglycemia, premeal insulin doses should be decreased by 50% when pramlintide is initi-ated. Liraglutide lowers fasting and postprandial blood glucose; it is not approved for use with insulin, although it is used off-label, especially with basal insulin. Even though the use of metformin has an insulin-sparing ef-fect, it primarily lowers FBG. Bromocriptine has a very modest reduction in fasting and postprandial blood glu-cose and is not approved for use with insulin.

4. Answer: DWhen an oral agent is no longer keeping a patient with type 2 DM at goal, addition, not substitution, of oral therapy is required (making Answer B incorrect). Be-cause this patient has elevated postprandial blood glu-cose levels, treatment designed to target postprandial glucose is required. Sitagliptin primarily lowers post-prandial blood glucose and is therefore the appropriate answer. Bedtime NPH insulin and metformin primarily lower fasting sugars, and increasing the dose of met-formin from 2000 mg to 2550 mg will have minimal additional glucose-lowering effects.

5. Answer: BThe empiric insulin dose in type 1 DM is 0.5 unit/kg, with half as bolus insulin and half as basal (NPH, de-temir, or glargine) insulin. This patient’s empiric basal insulin requirement is 20 units, thereby eliminating choices A and D . Glargine causes less hypoglycemia than NPH, therefore choice B is best .

6. Answer: DBecause B.L. uses a rapid-onset (lispro) insulin, the rule of 1800 applies (the rule of 1500 applies to regular insulin use). Taking 1800 and dividing it by B.L.’s total daily insulin dose (100) is equal to 18 mg/dL.

7. Answer: CTo calculate B.L.’s insulin-to-carbohydrate ratio, his total daily insulin dose (100 units) is divided into 500 (the rule of 500). In this case the best approximation of B.L.’s insulin-to-carbohydrate ratio is 5 g of carbohy-drates per unit of insulin (500/100 = 5).

8. Answer: AWith an insulin sensitivity index of 18 mg/dL, B.L. will need 3 units (54/18) to cover his premeal high blood glucose (184 − 130 = 54/18 = 3). He will require an ad-ditional 12 units (60 g divided by an insulin-to-carbo-hydrate ratio of 1 unit of insulin for every 5 g of car-bohydrates) to appropriately cover his meal. The best approximation of his total insulin dose will be 3 + 12 = 15 units.

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AnSwERS AnD ExPLAnATIOnS TO SELF-ASSESSMEnT QUESTIOnS

1. Answer: CE.G. has high premeal blood glucose values, which rep-resent poor postprandial glucose control. Because his A1c is 7.9% and his FBG values are reasonable, adding a postprandial agent is indicated. This would eliminate glargine because it targets FBG values. Sitagliptin has more convenient dosing and is as effective as, and much better tolerated than, acarbose. In addition, acarbose is contraindicated in patients with inflammatory bowel disease. E.G.’s estimated CrCl is greater than 50 mL/minute, so continuing metformin is reasonable.

2. Answer: CC.A.’s pre-supper blood glucose values are too high, which represents poor post-lunch glucose control. These blood glucose values are most affected by the morning NPH dose, which should be increased. Increasing the evening regular insulin will help cover these high read-ings but will not prevent future high readings. Adding a prelunch regular insulin dose will decrease the pre-supper blood glucose but at the cost of an additional injection.

3. Answer: BMixed insulin may be more convenient for patients to use; however, it is not as titratable as the use of two single insulins. For many patients, insulin needs do not match the ratio of the commercially available insulins. As a result, titration of insulin doses to correct one problem often results in too high or too low blood glu-cose readings at another time. In this case, the patient is receiving the equivalent of 60 units of intermediate-acting insulin and 20 units of quick-acting insulin each day. The almost-daily midmorning hypoglycemic re-actions are caused by too much (10 units) quick-acting insulin in the morning (Humalog 75/25 dose). Reduc-ing the morning dose will alleviate the midmorning low glucose but will also cause a rise in the pre-supper (postlunch) blood glucose. Eating more calories as car-bohydrates at breakfast will help prevent the midmorn-ing hypoglycemia but at the expense of weight gain. The recommendations for converting twice-daily NPH to insulin glargine call for using 80% of the original NPH dose (0.8 x 60 = 48 units). To prevent further mid-morning hypoglycemia, the morning quick-acting insu-lin dose should be less than 10 units.

4. Answer: CThe quickest-acting insulins consist of the insulin ana-logs lispro (Humalog), aspart (NovoLog), and glulisine (Apidra). Regular insulin is the next quickest-acting insulin. Neutral Protamine Hagedorn insulin has an intermediate duration of action, followed by the long-acting insulin analog detemir (Levemir) and the lon-gest-acting glargine (Lantus). Therefore, Answer C is correct.

5. Answer: APramlintide is an amylin analog, but unlike exenatide, it is not an incretin. Pramlintide does everything exena-tide does except increase insulin secretion.

6. Answer: DGlyburide, nateglinide, and sitagliptin are all secreta-gogues; however, of the three, only sitagliptin causes an increase in insulin secretion in a glucose-dependent manner, thereby minimizing the risk of hypoglycemia. Although metformin is typically a first-line choice for most people with type 2 DM, the drug is contraindicated in patients with poor renal function. Even with a normal serum creatinine, A.B.’s renal function at age 84 would preclude her from receiving metformin because of an increase in risk of the development of lactic acidosis.

7. Answer: BThe ACEIs decrease proteinuria, increase the time to doubling of serum creatinine, and delay the need for kidney transplantation and dialysis. Although aspirin reduces CV risk, it has no effect on the progression of renal disease. A high-protein diet can exacerbate renal insufficiency. Blood pressure reduction will delay the progression of renal disease in hypertensive patients. However, non–DHP-CCBs (diltiazem and verapamil) decrease proteinuria independently of the BP effect, whereas DHP-CCB can exacerbate proteinuria in pa-tients with well-controlled BP not receiving RAAS (renin-angiotensin-aldosterone system) suppression.

8. Answer: DThe ABC’s of diabetes care (aspirin use, A1c reduction, BP control, cholesterol control, and cessation of smok-ing) are designed to address the risk factors associated with macrovascular disease.

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