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 hyperglycemia 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 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. Aff ected 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. Type 2. Type 2 diabetes mellitus (T2DM) is the most common form of DM and is typically identifi ed 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). Th ose 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. Gestational diabetes mellitus. Gestational diabetes mellitus (GDM) is a condition in which women fi rst exhibit levels of elevated plasma glucose during pregnancy. Women previously diag- nosed with diabetes prior to pregnancy are excluded from this classifi cation. Aft er pregnancy, the diagnostic classifi cation of GDM may be changed based on postpartum testing (see III.B.2.b). Other specific types. Secondary diabetes occurs when the diagnosis of diabetes is a result of other disorders (e.g., Cushing syndrome, acromegaly, cystic fi brosis, Down syndrome, pancreatic 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. 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 classifi ed as having prediabetes. Prediabetes is a high-risk category for the future development of T2DM. 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:

Promotes the cellular uptake of plasma glucose Stimulates conversion of glucose into energy storage molecules (e.g., glycogen, fat) in the liver, muscles, and adipose cells 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. Th e counter- regulatory hormones include: Glucagon Growth hormone Catecholamines (epinephrine and norepinephrine) 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: Increases glucose-dependent insulin secretion Inhibits inappropriate glucagon secretion Increases -cell growth/replication Slows gastric emptying Suppresses appetite 4. Amylin is a hormone that is cosecreted with insulin from the pancreatic -cells. Thus, in individuals with T1DM, little to no amylin is produced, whereas in T2DM, amylin is produced, but in an insuffi cient quantity. Amylin lowers postprandial blood glucose levels by the following actions: Prolongs gastric emptying time Decreases postprandial glucagon secretion Suppresses appetite B. Development of diabetes 1. T1DM. Genetic predisposition o The risk of developing T1DM is increased in the off spring of individuals diagnosed with diabetes environmental factors o viral (e.g., rubella, Coxsackie B), chemical, or dietary (e.g., cows milk and autoimmunity o result of immune-mediated destruction of the -cells and is characterized by the abrupt onset of clinical signs and symptoms o Anti-insulin or anti--cell antibodies are present in the blood of most individuals at the time of diagnosis of T1DM 2. T2DM. Genetics Th e risk of off spring development of T2DM is at least 15%.

A primary -cell dysfunction only about 50% of -cells are functioning. A peripheral site defect o 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 fi brosis, Down syndrome, pancreatic disorders) or treatments (e.g., glucocorticoids, a ntipsychotics).

III. CLINICAL EVALUATION A. Physical findings include: polys (e.g., polyuria, polydipsia, and polyphagia), weight loss blurred vision Fatigue Headache frequent vaginal infections and poor wound healing. B. Diagnostic testing A1c tests o reflect the average blood glucose level over the preceding 2 to 3 months o not be done in individuals with abnormal red cell turnover (e.g., pregnancy, recent blood loss or transfusion, some anemias). 1. Diabetes in nonpregnant adults and children Fasting blood glucose 126 mg/dL Random (casual) blood glucose and symptoms of hyperglycemia: 200 mg/dL Oral glucose tolerance test (OGTT) using oral glucose load equivalent to 75 g anhydrous glycerin dissolved in water: 200 mg/dL A1c 6.5% 2. Gestational diabetes mellitus (GDM) screening should occur between weeks 24 to 28 gestation if not previously diagnosed with overt diabetes. Diagnosis of GDM based on OGTT: Fasting 92 mg/dL; 1 hr 180 mg/dL; 2 hrs 153 mg/dL. 3. Prediabetes: relatively high risk for the future development of diabetes Impaired fasting glucose (IFG): fasting blood glucose 100 to 125 mg/dL Impaired glucose tolerance (IGT): OGTT results of 140 to 199 mg/dL A1c 5.7 to 6.4% 4. Testing in asymptomatic individuals: a. Adults who are overweight (BMI 25 kg/m2). Risk factors for diabetes include: Physical inactivity First degree relative with diabetes 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 Hypertension ( 140/90 mm Hg or on therapy for hypertension)

HDL cholesterol level 35 mg/dL and/or a triglyceride level 250 mg/dL Women with polycystic ovarian syndrome (PCOS) Previous testing indicative of prediabetes Clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) 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) children who are overweight and have at least two risk factors IV. GLYCEMIC TREATMENT GOALS. Techniques for monitoring glycemic control : patient self-monitoring blood glucose (SMBG) o include fasting plasma glucose (FPG) and 2-hr postprandial glucose (PPG) A1c.

V. PHARMACOLOGIC TREATMENT OF DIABETES MELLITUS A. 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. e. Premixed insulin products. 50/50 insulin: 50% protamine lispro insulin with 50% lispro insulin 70/30 insulin: 70% insulin aspart protamine with 30% aspart insulin or 70% NPH with 30% regular insulin 75/25 insulin: 75% protamine lispro insulin with 25% lispro insulin f. Extemporaneous mixtures. Two insulins mixed in one syringe, before administration. Glargine and detemir should never be mixed in the same syringe with another insulin. When rapid-acting insulins (e.g., lispro, aspart, glulisine) are mixed with another insulin, the preparation should be used immediately. Extemporaneous mixtures which include regular-acting and intermediate-acting insulin are stable for 14 days refrigerated or 7 days at room temperature. 3. 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.

4. Mechanism of action. Insulin exerts its eff ects in several ways, including the following: Stimulates hepatic glycogen synthesis Increased protein synthesis Facilitates triglyceride synthesis and storage by adipocytes; inhibits lipolysis Stimulates peripheral uptake of glucose B. Insulin secretagogues (oral hypoglycemic agents) 1. Agents Sulfonylureas generally target fasting blood glucose levels and are classifi ed as first- or secondgeneration agents. o The three agents in this class i nclude tolbutamide (Orinase), tolazamide (Tolinase), and chlorpropamide (Diabinese) o (Second generation: (a) Glyburide (DiaBeta, Glynase) (b) Glipizide (Glucotrol) (c) Glimepiride (Amaryl) o Meglitinides: Repaglinide (Prandin) o Phenylalanine derivatives: Nateglinide (Starlix) 2. Indication: The secretagogues are indicated for the management of T2DM only. sulfonylureas is overall glycemic control,traditionally been seen as a fi rst-line agent for the management of T2DM meglitinide and phenylalanine derivative target postprandial control. 3. Contraindications: Individuals with severe renal or hepatic dysfunction Caution should be used in the elderly 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. Patient education and other concerns: a. Hypoglycemia b. Weight gain, secondary to increased insulin secretion, can occur. C . Biguanides 1. Agents: The only available biguanide is metformin (Glucophage, Glucophage XR, Fortamet, G lumetza, Riomet). 2. Indication:

used for the glycemic management of T1DM or T2DM recommended to be initiated at diagnosis of T2DM unless there is an existing contraindication. primarily targets fasting blood glucose levels.

3. Contraindications Renal disease: the potential for lactic acidosis. Hepatic impairment or those with alcoholism or binge drinking Heart failure: Intravascular iodinated contrast media 4. Mechanisms of action: inhibit hepatic glucose output, thus promote glucose uptake by fat and muscles, thereby improving insulin sensitivity. a minor role in decreasing intestinal absorption of glucose. 5.. Patient education and other concerns by GI eff ects (e.g., abdominal b loating, nausea, cramping, feeling of fullness, loss of appetite, or diarrhea). GI eff ects are self-limiting over 7 to 14 days. Minimal weight loss can be seen initially with this agent, but is not a continued effect. Metformin use has been associated with a reduction in vitamin B12 levels Miscellaneous eff ects include sweating and a metallic taste.

D. Thiazolidinediones (TZDs) 1. Agents: Pioglitazone (Actos) Rosiglitazone (Avandia) 2. Indication: glycemic control in T2DM and primarily affect the fasting blood glucose levels. 3. Contraindications 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 fi rst became available, LFTs had to be monitored every 2 months during the fi rst 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 thereaft er. b. Class III/IV heart failure: TZDs may cause fl uid 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. Th is 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). 5. Administration and dosage (Table 46-3) Table 46-3 Continued. Agent Initial Dose (Maximum Dose) Comments Amylin Agonists Pramlintide (Symlin) T1DM: 15 mcg immediately prior to meals (60 mcg t.i.d.) T2DM: 60 mcg immediately prior to meals (120 mcg t.i.d.) Adverse effects: nausea/vomiting, increased risk of severe hypoglycemia in persons with T1DM within 3 hrs of dosing 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 Drugdrug interactions: oral medications needing rapid onset (e.g., analgesics) should be administered 1 hr before or 2 hrs after pramlintide Targets postprandial blood glucose aConsult 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, creatinine 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. Diabetes Mellitus 941 6. Patient education and other concerns a. TZDs as a class cause signifi cant weight gain that is likely associated with fl uid retention and fat accumulation. Report unusual weight gain, shortness of breath, or swelling of the lower extremities. b. Benefi ts may not be seen prior to 2 to 4 weeks of use, with maximum eff ectiveness 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 3. Contraindications a. Infl ammatory 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. 5. Administration and dosage (Table 46-3) 6. Patient education and other concerns a. -glucosidase inhibitors cause increased gas formation in the colon, which can result in fl atulence. b. Th e dose should be taken with the fi rst bite of the meal for eff ectiveness. 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 eff ects 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. 3. Contraindications 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. 5. Administration and dosage (Table 46-3) 6. Patient education and other concerns 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 diffi culty breathing. G. Bile acid sequestrant 1. Agent: Colesevelam (Welchol) 2. Indication: adjunctive therapy for the management of T2DM 3. Contraindications 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 eff ects 942 Chapter 46 V. G 4. Mechanism of action for improved glycemic control is unknown. 5. Administration and dosage (Table 46-3) 6. Patient education and other concerns a. Oral medications should be taken 1 hr before or 4 hrs aft er colesevelam. b. Constipation is the most common adverse eff ect. 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 aff ect circadian rhythms, which may play a role in obesity and insulin resistance. 5. Administration and dosage (Table 46-3) 6. Patient education and other concerns 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 aft er 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 3. Contraindications 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 t hyroid 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 g lucose output, increases -cell growth and replication, slows gastric emptying, and enhances satiety. 5. Administration and dosage (Table 46-3) 6. Patient education and other concerns 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 eff ect. Weight loss is a sustained eff ect unrelated to gastrointestinal eff ects. d. Report unusual lump or swelling of the neck, diffi culty 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 Diabetes Mellitus 943 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 5. Administration and dosage (Table 46-3) 6. Patient education and other concerns 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 effi cacy 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 aft er 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 eff ects. 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. Th e SGLT2 inhibitors are proposed to inhibit this transporter, thus increasing the urinary excretion of glucose and lower- ing blood glucose levels. Th ese 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 dapaglifl ozin, serglifl ozin, and remoglifl ozin. 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. Th e 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. Th erapy with data to delay or prevent the disease progression include metformin, pioglitazone, orlistat, and alpha-glucosidase inhibitors (e.g., miglitol, acarbose). VIII. HYPERGLYCEMIC EMERGENCIES. Th e two most common hyperglycemic emergencies are diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). DKA and HHS diff er in the presence of ketoacidosis and the degree of hyperglycemia (Table 46-4). A. DKA, which is caused by profound insulin defi ciency, 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 defi ciency 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 fl uid losses, dehydration, and electrolyte depletion. 2. Precipitating factors: illness or infection, inadequate dosing of insulin or discontinuation of insulin 3. Signs and symptoms oft en 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 fi ndings 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 fl uids, insulin, potassium, and/or sodium bicarbonate. B. HHS predominantly aff ects 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 aff ect the elderly

individual. 1. Pathophysiology: Th e pathogenesis of HHS is not as clear as DKA. However, HHS does diff er from DKA in that insulin defi ciency 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, abdominal pain) Present Negative 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. 3American Diabetes Association. Position statement: Hyperglycemic crises in patients with diabetes. Diabetes Care 2003;26:s109117. Diabetes Mellitus 945 Individuals with HHS do have osmotic diuresis that produces dehydration, electrolyte depletion, and hypotonic fl uid loss to a greater extent than seen in DKA. 2. Precipitating factors: illness or infections, hypertonic feedings, excessive fl uid 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 fi ndings 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 fl uid replacement to avoid fl uid overload in elderly individuals. IX. HYPOGLYCEMIA. Hypoglycemia is the limiting factor for providing aggressive insulin therapy in individuals with T1DM or T2DM. A. Defi nition. Hypoglycemia is diffi cult to defi ne, 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, c onfusion, 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. Th e blood glucose level should be rechecked 15 to 20 mins aft er 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 individuals 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 eff ects 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 signifi cant 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. Th ese 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: Th e 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 oft en the result of ne- phropathy, whereas in T2DM, it is part of the conglomeration of cardiovascular risk factors. Th e 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 modifi cations 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 signifi cantly 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 benefi ts 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 benefi ts. 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 signifi cant 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. Classifi cation: Retinopathy may be classifi ed 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 thereaft er. 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 Diabetes Mellitus 947 used to estimate the glomerular fi ltration rate (GFR) and stage the level of chronic kidney disease (CKD). a. Albumin-to-creatinine ratio in random spot collection can be used to screen for microalbu- minuria or macroalbuminuria. (1) Classifi cation (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 6month period to classify an individual as having microalbuminuria or macroalbuminuria, due to the variability in urinary albumin excretion. Levels may be aff ected by exercise within 24 hrs, infection, fever, heart failure, or signifi cant 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 fi rst diminished in the toes and feet, then in the fi ngers and hands. Aff ected 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 monofi lament 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 u nawareness. 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 aff ected. 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 signifi cant lifestyle changes, including dietary changes and activity implementation. Lifestyle changes can oft en be diffi cult and therefore require positive reinforcement and involvement of the person with diabetes in the decision-making process. A. Medical Nutrition Th erapy (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 diff erent 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 signifi cant amount of carbohydrates (e.g., breads, milk, fruit, rice, beans, corn, and potatoes) 948 Chapter 46 XI. A 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. Th e plate method is a tool to provide portion control with healthier food group choices. Th e con- cept is to divide and fi ll 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 modifi able risk factors to minimize or prevent the development of chronic c omplications 1. Achievement of glycemic, lipid, and blood pressure goals 2. Smoking cessation 3. Reduction in weight, if appropriate E. Pattern control to determine eff ect of sickness, dietary choices, stress, and physical activity on ability to attain and maintain glycemic goals. F. Implementation of specifi c 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. Th e 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 fi tted 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 fi led. 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 aft er 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 diff er based on size of insulin syringe barrel chosen. Barrel sizes include 0.25-, 0.3-, 0.5-, and 1.0-mL capacity. plate of nonstarchy vegetables plate of meat plate of starch 1 fruit serving Sugar-free beverage Figure 46-1. The plate method. Diabetes Mellitus 949 Th e 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 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. Th us, 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 important 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. 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 aft er taking insulin (3) 2 or more hours aft er exercise b. Alternate site testing should not be used if: (1) Th e 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. Th is is only a partial list of potential drug interactions that may aff ect glycemic control. Consult standard references or drug package inserts for more detailed information. A. Potential hyperglycemia, as a dose-dependent, direct glucogenic eff ect. Corticosteroids, nicotinic acid, phenytoin, pentamidine (long-term eff ect), protease inhibitors, sympathomimetics, isoniazid, furosemide, thiazide diuretics B. Potential hypoglycemia, as a direct hypoglycemic eff ect; monoamine oxidase (MAO) inhibitors, fl uoxetine, salicylates (large doses), fenfl uramine, alcohol, pentamidine (initial eff ect) 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-infl ammatory drugs (NSAIDs), methyldopa, chloramphenicol, MAO inhibi- tors, clofi brate, probenecid 950 Chapter 46 Study Questions Directions: Each of the questions, statements, or incomplete statements in this section can be correctly answered or completed by one of the suggested answers or phrases. Choose the best answer. 1. Which patient meets the diagnostic criteria for diabetes, assuming tests were taken on separate visits? (A) An elderly female with fasting blood glucose values of 102 mg/dL and 132 mg/dL. (B) A teenage boy with a fasting blood glucose of 128 mg/dL and an A1c of 6.6%. (C) A 10-year-old girl with a random blood glucose value of 180 mg/dL and 190 mg/dL. (D) A morbidly obese male with a random blood glucose value of 102 mg/dL and an oral glucose tolerance test result of 160 mg/dL. 2. A 45-year-old obese female has just been diagnosed with diabetes. Otherwise, she is healthy with no other medical conditions. Her blood pressure today is 110/75 mm Hg; spot urine microalbumin 30; TC 180; HDL 32; LDL 122; TG 150. Based on ADA guidelines, which should be started today? (A) Aspirin 81 mg daily (B) Pravastatin 10 mg daily (C) Lisinopril 10 mg daily (D) Irbesartan 150 mg daily 3. A patient is currently on a regimen of Humalog Mix 70/30, 24 units in the morning and 12 units in the evening. Based on the following averages obtained from his blood glucose meter, which would be the most appropriate recommendation for his glycemic control today? Pre-Breakfast: 220 mg/dL Pre-Lunch: 110 mg/dL PreSupper: 90 mg/dL Bedtime: 108 mg/dL 3 am: 62 mg/dL (A) Increase evening dose of Humalog Mix to 15 units (B) Decrease evening dose of Humalog Mix to 10 units (C) Continue current regimen without changes (D) Increase morning dose of Humalog Mix to 28 units (E) Decrease morning dose of Humalog Mix to 20 units 4. A 222-lb male presents to the diabetes care team for routine diabetes management. His fi ngerstick blood glucose value is 452 mg/dL (445 mg/dL on repeat) and his urine is negative for ketones. Per clinic protocol, he may be treated in the offi ce for hyperglycemia. Which is the most appropriate treatment to bring his blood glucose to a target of 120 mg/dL? (A) Glargine 20 units (B) Lispro 60 units (C) Aspart 30 units (D) Glulisine 11 units (E) Detemir 24 units 5. A 400-lb male has just been diagnosed with type 2

diabetes. His A1c is greater than 15% and his kidney and liver function are normal. Which would be the most appropriate initial agent for monotherapy? (A) Metformin 850 mg q.d. (B) Pioglitazone 30 mg q.d. (C) Glargine 36 units q.d. (D) Liraglutide 0.6 mg q.d. (E) Glimepiride 4 mg q.d. 6. An individual with T2DM currently takes metformin XR 500 mg 2 b.i.d., pioglitazone 45 mg, and glimepiride 4 mg b.i.d. He takes his morning medications at 8 a.m. with breakfast and his evening medications at 6 p.m. with supper. He does not eat lunch. He brings in his log book and meter today, which reveal multiple hypoglycemic events (45 to 62 mg/dL) around 1 p.m. to 2 p.m. His A1c today is 6.0%. Which would be the most appropriate recommendation for glycemic control at this time? (A) Discontinue morning dose of metformin (B) Discontinue evening dose of metformin (C) Discontinue daily dose of pioglitazone (D) Discontinue morning dose of glimepiride (E) Discontinue evening dose of glimepiride 7. A 64-year-old female is taking metformin, pioglitazone, and sitagliptin for T2DM. Her liver function tests were elevated (AST 132 u/L and ALT 140 u/L) and she tested positive for Hepatitis C. Which is the best recommendation at this time? (A) Discontinue metformin only (B) Discontinue pioglitazone only (C) Discontinue sitagliptin only (D) Discontinue metformin and pioglitazone (E) Discontinue all agents for glycemic control Diabetes Mellitus 951 8. Which best describes the mechanism of action of repaglinide? (A) Insulin secretagogue (B) Insulin sensitizer (C) DPP-IV inhibitor (D) GLP-1 agonist (E) -glucosidase inhibitor 9. A patient has been hospitalized for the past 3 days following a severe asthma exacerbation, but is being discharged today. He weighs 228 lb, but he has no previous history of diabetes. Blood work today shows a random blood glucose of 320 mg/dL and an A1c of 5.2%. His current medication list includes albuterol nebules, prednisone, pulmicort, and oxygen. Which statement is most appropriate? (A) Th e patient has diabetes and should be discharged on an insulin regimen. (B) Th e patient has hyperglycemia induced by his inhaled corticosteroid. (C) Th e patient has hyperglycemia induced by his agonist. (D) Th e patient has hyperglycemia induced by his oral glucocorticoid. 10. A patient currently takes Amaryl, Actos, Januvia, and Lantus. He presents to the clinic today concerned about the swelling in his lower extremities, signifi cant weight gain, and shortness of breath. Which is the most likely cause of presenting symptoms? (A) Amaryl (B) Actos (C) Januvia (D) Lantus 11. A person newly diagnosed with T1DM will need to start an insulin regimen. Based on her weight of 100 lb, which would be the most appropriate basal regimen? (A) Levemir 13 units daily (B) Lantus 27 units daily (C) Novolog 4 units three times daily (D) NPH 15 units once daily (E) U-500 1.5 mL twice daily 12. Which formulation is the best recommendation for a patient needing an intravenous insulin infusion? (A) Regular insulin, U-500 (B) Regular insulin, U-100 (C) NPH insulin, U-100 (D) Aspart insulin, U-100 (E) Aspart insulin, U-400 13. A patient presents for treatment of his type 2 diabetes mellitus (T2DM). His A1C is 7.2% and he has hepatitis C (AST 150 units/L; ALT 132 units/L), hypertension, dyslipidemia, rheumatoid arthritis, and mild renal impairment (SCr 1.6). Which would be the best initial agent at this time? (A) saxagliptin (B) metformin (C) pioglitazone (D) glulisine 14. An obese woman (350 lb) has used metformin 1000 mg bid to control her T2DM for the past 2 years. Her A1C today is 8%. Which would be the most appropriate

recommendation to improve glycemic control without providing further weight gain? (A) sulfonylurea (B) thiazolidinedione (C) GLP-1 agonist (D) amylin agonist 15. All of the following are correct statements about metformin except (A) metformin may cause renal impairment. (B) metformin should not be used in patients who are alcoholic. (C) metformin should be discontinued in women with a SCr 1.4. (D) metformin may cause vitamin B12 depletion. 16. A patient takes neutral protamine Hagedorn (NPH) 16 units bid and regular insulin 6 units bid. Based on her average blood glucose values below, what is the best recommendation for adjusting her insulin regimen? (A) fasting: 82 mg/dL (B) pre-lunch: 180 mg/dL (C) pre-supper: 110 mg/dL (D) bedtime: 98 mg/dL 17. A patient has been using continuous intravenous i nsulin infusion at 0.8 units/hr with steady control aft er being diagnosed with type 1 diabetes mellitus (T1DM). He is to be discharged from the hospital with prescriptions for detemir and glulisine. When is the most appropriate time to initiate the detemir? (A) 30 minutes prior to discontinuing the continuous insulin infusion (B) 1 hour prior to discontinuing the continuous insulin infusion (C) 2 hours prior to discontinuing the continuous insulin infusion (D) 1.5 hours aft er discontinuing the continuous insulin infusion (E) 3 hours aft er discontinuing the continuous insulin infusion 952 Chapter 46 Answers and Explanations 1. Th e answer is B [see III.B]. Regardless of age or gender, diagnostic criteria for dia- betes in the nonpregnant individual is a positive of at least two of the following values: random blood glu- cose 200 mg/dL; fasting blood glucose 126 mg/ dL; OGTT 200; A1c 6.5%. 2. Th e answer is B [see X.A.1]. Based on ADA guidelines, aspirin should be initiated for primary prevention in women greater than age 60; statin therapy should be initiated in patients with overt CVD or any patient over the age of 40 without overt CVD, but with other CVD risk factors; ACEI and ARBs are recommended for blood pressure control if necessary (not needed here) and when urine microal- bumin is 30. 3. Th e answer is B [see Table 46-2; V.A.8.b]. Increasing the morning dose will only lower the lunch and supper readings further. Increasing the evening dose will lower the 3 a.m. even more. Th is patient is most likely experiencing rebound hyperglycemia (Symogyi) as evidenced by the hypoglycemia at the 3 a.m. readings and elevated fasting readings pre-breakfast. 4. Th e answer is D [see V.A.7.a]. Th e blood glucose needs to come down rapidly in- offi ce, thus he would not choose glargine or detemir as agents due to their longer onset of action. Lispro, aspart, and glulisine would all be appropriate choices, but the dose should be based on the pointof-care cor- rection equation ([Current blood glucose-Target blood glucose]/CF). Steps to solve: 1. Weight in kg: Weight is 222lb 101 kg 2. Determine TDD: (101)(0.6) 60 3. Determine CF: 1800/60 30 4. Plug into equation: (452120)/30 11 units 5. Th e answer is C [see VI.A.1.c]. Metformin would typically be the initial agent of choice in a patient diagnosed with type 2 diabetes. However, with this patients A1c greater than 15%, insulin is the most appropriate choice. Metformin can be started in addition to the insulin, but not as monotherapy. Oral agents and non-insulin injections will bring the A1c down no greater than 1%.

6. Th e answer is D [see V.B.1.a; Table 46-3]. Th e pharmacologic agent most responsible for causing hypoglycemia is the sulfonylurea (glimepiride), which is compounded by the fact that the patient does not eat lunch. Th e morning dose of glimepiride would peak around lunch time when food intake should be occur- ring. In the absence of lunch, hypoglycemia results. 7. Th e answer is D [see V.C.3.b; V.D.3.a; V.F]. Metformin and pioglitazone should not be used in a patient with liver disease and elevated LFTs. Sitagliptin may be used in hepatic impairment. When the LFTs go back to a normal range, it can be considered to reiniti- ate metformin and pioglitazone. 8. Th e answer is A [see V.B.1.b]. Repaglinide is a meglitinide, which works to produce a rapid burst of insulin secretion from the pancreas. 9. Th e answer is D [see III.B; XIII.A]. Inhaled corticosteroids have no eff ect on the blood glu- cose of an individual without diabetes and agonists have no eff ect. However, oral steroids, such as predni- sone can induce signifi cant hyperglycemia, particu- larly in the midaft ernoon when dosed in the morning. 10. Th e answer is B [see V.D.6.a; Table 46-3]. Patients taking a TZD such as Actos should be moni- tored for peripheral edema, weight gain, and shortness of breath due to its propensity to cause or worsen heart failure. 11. Th e answer is A [see V.A.6.a]. NovoLog is not a basal insulin and U-500 is reserved for patients with severe insulin resistance. NPH is dosed twice daily. Basal insulin should be initiated at 50% of TDD. TDD is 27 units, which gives 13.5 units as basal. 12. Th e answer is B [see V.A.9.b]. Regular insulin, U-100 is the most logical choice for an IV infusion. Aspart may be given in an emergency preparedness situation, but should not be given routinely due to the additional cost above that of regular U-100 insulin. 13. Th e answer is A [see V.F.2; VI.A.1.a]. 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. Diabetes Mellitus 953 14. Th e answer is C [seeV.B.6.b; V.D.6.a; Table 46-3]. Both sulfonylureas and TZDs have the potential to increase weight, whereas GLP-1 agonists and amylin agonists can provide weight loss. Amylin agonist is not appropriate because it should only be added aft er a basal and bolus insulin have been added. 15. Th e answer is A [see V.C.3.a]. Metformin should not be used in patients with renal disease, but the metformin itself does not cause renal impairment. 16. Th e answer is B [see V.A.8; Table 46-2]. Increasing morning NPH will cause further decrease of presupper reading. Increasing evening doses of in- sulin will cause fasting blood glucose to be too low. 17. Th e answer is C [see V.A.9.b.(2)]. Long-acting insulin should be injected 2 hours prior to discontinuation of a continuous insulin infusion to allow adequate onset time.