13. Diabetes Mellitus - Joni Foard, PharmD, CDE, L. Brian Cross, PharmD, CDE

13-1. Overview


Diabetes mellitus (DM) is a group of chronic metabolic diseases caused by defects in insulin secretion, action, or both that result in hyperglycemia; abnormal metabolism of carbohydrates, fats, and proteins; and long-term macrovascular and microvascular complications.

DM affects 23.6 million people or approximately 8% of the population: 17.9 million diagnosed and 5.7 million undiagnosed.

It is the seventh-leading cause of death. Risk of death is two times that of people without diabetes of similar age.


Type 1 diabetes

Type 1 diabetes was previously called insulin-dependent diabetes mellitus or juvenile-onset diabetes. It requires exogenous insulin for survival. It comprises 5-10% of all diagnosed cases.

Type 2 diabetes

Type 2 diabetes was previously called noninsulin-dependent diabetes mellitus or adult-onset diabetes. It comprises 90-95% of all diagnosed cases.

Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) involves glucose intolerance with onset of pregnancy or first recognition during pregnancy (second and third trimesters). Approximately 7% of pregnancies develop GDM: > 200,000 annually. Women with GDM have 40-60% chance of later developing type 2 diabetes; 5-10% of those are diagnosed in the postpartum period. The primary fetal complication of concern is macrosomia.

Other types: Secondary DM

Secondary DM is attributable to genetic defects of β-cell function (e.g., maturity-onset diabetes of youth), surgery, drugs, malnutrition, infections, and other illnesses. It comprises 1-5% of all diagnosed cases.


In prediabetes, plasma glucose levels are higher than normal but lower than those diagnostic for diabetes. Prediabetes was formerly characterized as impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). It is a risk factor for future diabetes and cardiovascular disease.

Clinical Presentation

Classic signs and symptoms include polydipsia, polyuria, and polyphagia. Other common findings include fatigue, blurred vision, and frequent infections.

Type 1 diabetes

Signs include rapid onset and unexplained weight loss. Patients are potentially ketonuric or experience ketoacidosis. They may experience a "honeymoon" period, a phase of erratic insulin secretion lasting months to a year during destruction of β-cells.

Type 2 diabetes

Onset is progressive. Patients may be asymptomatic or experience mild classic signs and symptoms; 80% are obese or have history of obesity. Patients may present with microvascular and macrovascular chronic complications

Pathophysiology and Etiology

Type 1 diabetes

• β-cell destruction leads to absolute insulin deficiency.

• Subgroups are as follows:

• Immune mediated, in which a strong human leukocyte antigen association indicates genetic predisposition. This subgroup is related to environmental factors; a stimulus (e.g., virus) triggers the immunologic process.

• Idiopathic, in which there is no evidence of autoimmunity or other known etiology.

• Patients are prone to ketoacidosis.

• Peak onset occurs at the time of puberty but may occur at any age.

Type 2 diabetes

• Insulin resistance and progressive β-cell dysfunction are characteristic.

• Development of type 2 DM often involves a strong genetic predisposition.

• It is also associated with environmental factors such as excessive calorie intake, decreased activity, weight gain, and obesity.

• Insulin resistance may be present years before the onset of diabetes.

• Initially normal glucose levels are maintained by increased insulin secretion by β-cells.

• Increasing insulin resistance or a failure of β-cells to maintain insulin secretion leads to glucose intolerance and development of diabetes.

• Insulin resistance is influenced by age, ethnicity, physical activity, medications, and weight.

• Type 2 DM is usually diagnosed in adulthood but can occur at any age.

• The incidence of type 2 diabetes is higher among certain ethnic populations (

Figure 13-1).

Diagnostic Criteria

Box 13-1 shows the criteria for the diagnosis of DM.

[Figure 13-1. Estimated Age-Adjusted Total Prevalence of Diabetes in People 20 Years or Older, by Race and Ethnicity: United States, 2005]


Symptoms of diabetes and a casual plasma glucose ≥ 200 mg/dL (11.1 mmol/L). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.


FPG ≥ 126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours.


Two-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

Source: Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97. Reprinted with permission from the American Diabetes Association.

Note: In the absence of unequivocal hyperglycemia, criteria should be confirmed by repeat testing on a different day.

Type 1 and type 2 DM

Diagnosis can be made on the basis of a fasting plasma glucose (FPG) test, a random plasma glucose test, or an oral glucose tolerance test (OGTT). Diagnosis must be confirmed on a subsequent day using any of the three methods.

The FPG test is the test of choice because of simplicity, lower cost, and reproducibility.

Abnormal results not meeting criteria outlined in Box 13-1 are classified as prediabetes:

• IFG = FPG ≥ 100 mg/dL to 125 mg/dL

• IGT = 2-hour OGTT plasma glucose ≥ 140 mg/dL to 199 mg/dL

Serum C peptide level is diagnostic for functioning of β-cells and may be used for classification.

Gestational diabetes mellitus

OGTT is preferred screening test in pregnancy. For average-risk patients, test at 24-28 weeks of gestation. For high-risk patients (marked obesity, personal history of GDM, glycosuria, diagnosis of polycystic ovarian syndrome, or strong family history of DM), perform a risk assessment at the first prenatal visit and test as soon as possible; if initial screenings are negative, retest between 24 and 28 weeks of gestation.

In average- or high-risk patients use one of two approaches:

• One-step approach: diagnostic 100 g OGTT

• Two-step approach: 1-hour 50 mg glucose challenge test followed by diagnostic 100 g glucose OGTT if 1-hour level ≥ 140 mg/dL

Diagnosis of GDM with a 100 g glucose load is positive if at least two glucose values meet or exceed the following levels:

• Fasting: ≥ 95 mg/dL

• 1 hour: ≥ 180 mg/dL

• 2 hours: ≥ 155 mg/dL

• 3 hours: ≥ 140 mg/dL

If on the subsequent day FPG ≥ 126 mg/dL or casual plasma glucose ≥ 200 mg/dL, a glucose challenge is not needed. Reevaluation and reclassification should be conducted 6-12 weeks postpartum.

Treatment Principles and Goals

• To achieve and maintain glycemic control (

Table 13-1)

• To attain recommended blood pressure and lipid goals (Table 13-1)

• To modify lifestyle to promote general health and achieve weight management goals

• To prevent or slow progression of chronic complications

• To prevent or resolve acute complications

• To achieve an acceptable quality of life and satisfaction with care

Prevention of complications

The following activities can prevent complications from arising:

• Smoking cessation

• Aspirin or antiplatelet therapy

• Use as secondary prevention with a history of cardiovascular disease.

• Use as primary prevention if patient is > 40 years of age or has additional risk factors (family history of cardiovascular disease, hypertension, smoking, dyslipidemia, or albuminuria).

• Prescribe aspirin 75-162 mg/d.

• Immunization

• Annual influenza vaccine if patient is 6 months of age or older and no contraindications

• At least one lifetime pneumococcal vaccine for adults with no contraindications

[Table 13-1. Summary of Recommendations for Adults with Diabetes]

• One-time pneumococcal revaccination if patient is > 64 years of age, previously immunized at < 65 years of age, and vaccine administered > 5 years ago

• Foot care: self-inspection daily, visual inspection at each office visit, and an annual comprehensive exam

• Skin care: self-inspection and care daily

• Dental care: annual examination

• Eye care: annual dilated eye examination

Complications of diabetes

Chronic complications

• Coronary atherosclerosis: Death rate is two to four times higher in adults with DM than in adults without diabetes.

• Cerebrovascular atherosclerosis: Risk of stroke is two to four times higher among people with diabetes.

• Peripheral vascular disease: Pain is due to intermittent claudication; insufficient circulation impairs healing and increases risk of gangrene and amputation.

Microvascular disease

• Retinopathy

• It is the leading cause of new cases of blindness in adults 20-74 years of age.

• Retinopathy may develop without symptoms; annual dilated eye examination is recommended for detection.

• Treatment includes glycemic and blood pressure control and laser photocoagulation.

• Nephropathy

• It occurs in 20-40% of diabetics and is the leading cause of end-stage renal disease.

• Random spot collection of the albumin-to-creatinine ratio should be performed yearly; a value of > 30 mg/g is considered abnormal.

• Serum creatinine should be measured at least annually for the estimation of glomerular filtration rate (GFR).

• Treatment includes glycemic and blood pressure control; angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers should be used except during pregnancy.

• Polyneuropathy

• Sensorimotor nervous system dysfunction occurs.

• Pain and diminished sensation occur, with potential for poor detection of trauma, which increases risk for ulcers and infection.

• Autonomic neuropathy

• Gastrointestinal (GI) effects include gastroparesis, constipation, and diarrhea.

• Genitourinary effects include neurogenic bladder and sexual dysfunction in men.

• Cardiovascular effects include orthostatic hypotension and resting tachycardia.

• Diabetic foot problems

• DM accounts for > 60% of nontraumatic amputations in the United States.

• Prevention, early detection with regular foot exams, and prompt treatment of lesions are essential to avoid complications.

Acute complications

• Hypoglycemia

• Hypoglycemia is defined as plasma glucose < 70 mg/dL.

• Glucose (15-20 g) is the preferred treatment, but other forms of carbohydrates that contain glucose can be used.

• Treatment effects should be seen in 15 minutes.

• Symptoms can range from mild (tremor, palpitations, sweating) to severe (unresponsiveness, unconsciousness, or convulsions).

• Severe hypoglycemia may require assistance from another individual for treatment with glucagon or IV glucose.

• Diabetic ketoacidosis (DKA)

• DKA is a medical emergency in type 1 diabetes because of absolute or relative insulin deficiency.

• Omission of insulin, major stress, infection, or trauma may precipitate DKA.

• DKA is characterized by glucose > 250 mg/dL, elevated ketones, arterial pH < 7.2, plasma bicarbonate < 15 mEq/L.

• Ketone bodies are formed in excess because of fatty acid metabolism in the liver, leading to ketonuria and ketonemia and ultimately diabetic ketoacidosis.

• Kussmaul respirations (deep and rapid) are characteristic in an attempt to compensate for metabolic acidosis.

• DKA requires prompt intervention with insulin, fluids, and electrolytes to prevent coma and death.

• Hyperosmolar hyperglycemic state

• It is also known as hyperglycemic hyperosmolar nonketotic coma.

• It is a complication of type 2 diabetes.

• The state is characterized by elevated plasma glucose (typically > 500 mg/dL), dehydration, and hyperosmolality in the absence of significant ketoacidosis.

• It may be triggered by infection or other stressors such as stroke or myocardial infarction.

• Treatment includes fluid and electrolyte replacement as well as insulin.

13-2. Drug Therapy

Oral Medications for DM Treatment


Mechanism of action

The primary mechanism of secretagogues is to cause a reduction in blood glucose by stimulating the release of insulin from the pancreas. This mechanism may in turn cause a decrease in hepatic gluconeogenesis and a slight decrease in insulin resistance at the muscle level. Effectiveness depends on pancreatic β-cell function.

Clinical and counseling considerations

• Medication should be taken before meals: sulfonylureas, qd bid; meglitinides, before each meal.

• Medication causes a 1-2 kg weight gain.

• A positive risk of hypoglycemia exists, which is greater with sulfonylureas than with meglitinides.

• Secretagogues are typically not indicated during pregnancy, when breast-feeding, or in children.

• A fast-acting oral carbohydrate should be carried for emergency use.

A1c reduction

• 1-2% (sulfonylureas)

• 0.5-2% (meglitinides)


• Medications are generically available.

• For meglitinides, the monthly cost is about $75-200.

Cautions and contraindications

• Use with caution in elderly patients; do not use chlorpropamide.

• Use with caution in cases of renal and hepatic insufficiency; glipizide and glimepiride safer.

• Avoid in patients with significant alcohol use.

• Drug interactions (worse with first-generation sulfonylureas) may cause increased risk of hypoglycemia: anticoagulants, fluconazole, salicylates, gemfibrozil, sulfonamides, tricyclic antidepressants, digoxin.

• Use is contraindicated in patients with DKA, severe infection, surgery, or trauma.

• Patients should wear medical identification.

• Store drug in a cool, dry place (not the bathroom or kitchen).

• Syndrome of inappropriate antidiuretic hormone secretion, disulfiram-like reaction with alcohol (ETOH), and sun-sensitivity reactions are more common in first-generation sulfonylureas than in second-generation sulfonylureas.



Table 13-2 for information about dosing.


Mechanism of action

The primary mechanism is seen through decreased hepatic gluconeogenesis as well as improved glucose

[Table 13-2. Sulfonylureas]

utilization and uptake in peripheral tissues and decreased intestinal absorption of glucose.

Clinical considerations

• Biguanides are considered the first choice when beginning drug treatment in newly diagnosed DM patients unless contraindicated.

• They pose minimal risk of hypoglycemia unless combined with secretagogues or insulin.

• They may decrease weight up to 5 kg.

• They decrease triglycerides, decrease LDL, and increase HDL.

• GI symptoms (nausea, vomiting, bloating, flatulence, anorexia, and diarrhea) are the most common adverse effects.

• Take doses with or after meals to reduce GI symptoms.

• GI symptoms are transient and improve in most patients over time.

• Titrate the dose up slowly to minimize GI symptoms: 500 mg qd with the largest meal × 1 week; then increase to 500 mg bid with the two largest meals × 1 week; then increase to 1 g (two 500 mg tablets) with largest meal and 500 mg with the second-largest meal × 1 week; then increase to 1 g bid with the two largest meals of the day.

• Biguanides interfere with vitamin B12 absorption.

• They may require as much as 8 weeks of therapy before effectiveness can be assessed.

• Biguanides are generally not indicated during pregnancy or breast-feeding.

• They are indicated for the treatment of type 2 DM in children 10 years and older.

• They may decrease the progression to diabetes from IGT and IFG (prediabetes).

• They have positive cardiovascular benefits when used in obese patients with DM.

A1c reduction

A reduction of 1-2% is expected.


Biguanides are generically available.

Cautions and contraindications

Most cautions and contraindications are related to the ability of biguanides to increase the risk of lactic acidosis with metformin (less than one case per 100,000 treated patients).


• Renal insufficiency (serum creatinine, or SCr ≥ 1.4 females; SCr ≥ 1.5 males) is a contraindication; recent studies have suggested that metformin is safe unless the estimated GFR falls to < 30ml/min.

• Hepatic dysfunction is a contraindication.

• Excessive alcohol use (binge or chronic use of more than two drinks per day or at one sitting) is a contraindication.

• Medication may be contraindicated in congestive heart failure (New York Heart Association classifications III and IV).


• Medication should be held back in situations of increased risk for lactic acidosis, including acute myocardial infarction, congestive heart failure exacerbation, severe respiratory disease, shock, and septicemia.

• Medication should be held back 48 hours after iodinated contrast media and major surgeries.



Table 13-3 for information about dosing.

Thiazolidinediones (glitazones/TZDs)

Mechanism of action

Thiazolidinediones (also called glitazones or TZDs) are agonists of the PPARγ (peroxisome proliferators-activated receptor-γ) receptor, which, when stimulated, improves peripheral muscle and adipose tissue insulin sensitivity as well as suppresses hepatic glucose output.

Clinical considerations

• Minimal risk of hypoglycemia exists unless combined with secretagogues or insulin.

• TZDs may cause a 5 kg weight gain—more if combined with secretagogues or insulin.

• They decrease triglycerides (pioglitazone > rosiglitazone), increase high-density lipoprotein (HDL) (pioglitazone = rosiglitazone), and increase low-density lipoprotein (LDL) (rosiglitazone)/LDL (pioglitazone).

• They are dosed qd, though rosiglitazone may be slightly more effective when dosed bid.

• As much as 16 weeks of therapy may be required before assessing effectiveness.

• Generally, they are not indicated during breast-feeding or pregnancy.

• They may decrease the progression to diabetes from IGT and IFG.

• Edema may best be treated by aldosterone antagonists.

• They are not indicated by the U.S. Food and Drug Administration for treatment of type 2 DM in children, though they have been used.

• They may be helpful in nonalcoholic fatty liver disease.

• Recent meta-analyses suggest a 30-40% relative increase in risk for myocardial infarction with rosiglitazone, though not with pioglitazone.

[Table 13-3. Biguanides]

A1c reduction

A reduction of 1-2% is expected.


The monthly cost of the medication is approximately $120-200.

Cautions and contraindications

• Edema—with oral therapies (approximately 5%), with insulin (approximately 15%)—may occur in patients with no history of heart problems. (The condition may be dose related.) Recommendation: Discontinue therapy if the problem is significant, decrease the dose if the problem is minor, and consider further cardiac workup.

• Recently, a black box warning was added for congestive heart failure (pioglitazone and rosiglitazone).

• Hepatotoxicity incidence is approximately 0.2% of alanine aminotransferase (ALT) > three times upper limit of normal (ULN) for both agents. Recommendation: Liver function tests (LFTs) every other month for first 12 months and periodically thereafter. If ALT > 2.5 ULN, do not start; if ALT = 1.0-2.5 ULN, monitor closely; if ALT 3× ULN, discontinue medication.

• Medication may cause resumption of ovulation in anovulatory women.

• Medication decreases oral contraceptive effectiveness.



Table 13-4 for information about dosing.

Alpha-glucosidase inhibitors

Mechanism of action

Alpha-glucosidase inhibitors delay the digestion of carbohydrates into simple sugars and their subsequent absorption in the small intestine.

Clinical considerations

• Minimal risk of hypoglycemia exists unless the drug is combined with secretagogues or insulin.

• Alpha-glucosidase inhibitors have minimal effect on weight but can cause possible decrease in weight secondary to side effects.

• Main target of therapy should be postprandial hyperglycemia.

• GI symptoms (flatulence, GI upset, abdominal pain, diarrhea, bloating) are the most common side effects. These side effects tend to dissipate over time with continued treatment. Dosing must be individualized and slowly titrated up as tolerated: 25 mg qd × 1 week; then 25 mg bid × 1 week; then 25 mg tid × 1 week; then continued increased dose as tolerated up to 50 mg tid.

• Patient should be counseled to increase complex carbohydrate intake and decrease intake of simple sugars.

• Treatment of hypoglycemia:

• Patient should use milk (lactose) or fruit juice (fructose), not sucrose.

• Any carbohydrate can be used if > 2-3 hours since last dose of alpha-glucosidase inhibitor agent.

• Alpha-glucosidase inhibitors are generally not indicated during pregnancy, while breast-feeding, or in children.

• Alpha-glucosidase inhibitors decrease the bioavailability of digoxin, propranolol, and ranitidine.

A1c reduction

A reduction of 0.5-1.0% is expected.


The monthly cost of the medication is approximately $75-100.

Cautions and contraindications

• Avoid use in patients with GI disorders such as ulcerative colitis, Crohn's disease, possible bowel obstruction, and short bowel syndrome.

[Table 13-4. Thiazoladinediones]


Table 13-5. Alpha-Glucosidase Inhibitors]

• Avoid use in patients with SCr > 2 mg/dL (acarbose) or creatinine clearance (CrCl) of ≤ 25mL/min (both agents).

• Increased LFTs may be needed (acarbose) depending on the dose (> 300 mg/day) and weight of patient. Avoid use in patients with cirrhosis.


See Table 13-5 for information about dosing.

Dipeptidyl peptidase—4 inhibitors

Mechanism of action

Dipeptidyl peptidase—4 (DPP-4) inhibitors inhibit the degradation of endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which in turn causes (1) increased insulin production in a glucose-dependent fashion, (2) decreased production of glucagon, and (3) improved β-cell functioning.

Clinical considerations

• Minimal risk of hypoglycemia exists unless drug is combined with secretagogues or insulin.

• These drugs have minimal or no effect on weight.

• They can be used either as monotherapy or in combination with metformin or thiazolidinediones and possibly with insulin.

• This is the only drug class affecting the GLP-1 system dosed orally.

• Generally, DPP-4 inhibitors are very well tolerated. The most common side effects include nasopharyngitis and upper respiratory tract infections.

• Secondary to newness of the drug, no significant long-term outcome data are yet available.

A1c reduction

A reduction of 0.6-0.9% is expected.


The monthly cost is about $150.

Cautions and contraindications

• The dose should be adjusted for renal insufficiency.

• The drug may cause adverse immunologic reactions through T-cell inhibition.

• The drug should not be used in patients with DKA or type 1 DM.



Table 13-6 for information about dosing.

Combination oral agents for DM

Figure 13-2 shows the combination oral agents for DM. See individual agents for details.

Injectable Medications for DM Treatment

Insulin products

Mechanism of action

At low levels, insulin causes suppression of endogenous hepatic glucose production. At higher

[Table 13-6. Dipeptidyl Peptidase-4 Inhibitors]

[Figure 13-2. Combination Oral Agents]

levels, insulin promotes glucose uptake by muscle tissue.

Clinical considerations

• Insulin carries a positive risk of hypoglycemia.

• It causes an increase in weight.

• Insulin should be considered as initial agent if glucose is > 250 mg/dL or A1c is > 10%.

• There is no dosage limit.

• Dosing is often started with a basal insulin (0.1-0.2 units/kg/d) and added to an existing oral regimen of two or more agents.

• Insulin regimen should be individualized to the patient accounting for

• Glucose readings

• Patient preferences

• Patient schedule

• Patient education and intelligence level

• Level of intensity needed

• Cost to patient

• Consider patient for prandial insulin coverage when

• Patient with fasting blood glucose target (< 100), but A1c ≥ 7%

• A1c ≥ 7% with evidence of frequent 2-hour postprandial glucose values > 160 mg/dL

• Nighttime or daytime hypoglycemia with skipped or delayed meals

A1c reduction

A reduction of 2.5% is expected.


Monthly cost varies, depending on the insulin product prescribed and the device used (i.e., pen versus vial or syringe).

Cautions and contraindications

• Dose cautiously in patients with renal and hepatic insufficiency.

• Dose cautiously in elderly patients.

• Do not mix the following insulins with any others: Lantus, Levemir, Lente, and Ultralente.

• Counsel patients on signs and symptoms of hypoglycemia and how to appropriately treat.

• Most insulin products are stable at room temperature for 30 days, other than premixed insulin products (14 days) and Levemir (45 days).


Table 13-7 provides sample titration schedules for basal and prandial insulin. See

Table 13-8 for further dosing information.

Incretin mimetics

Mechanism of action

Incretin mimetics are receptor agonists of endogenous GLP-1 that cause (1) increased insulin production in a glucose-dependent fashion, (2) decreased production of glucagon, (3) slowing of gastric emptying, (4) increased satiety and weight loss, and (5) improved β-cell functioning.

Clinical considerations

• Minimal risk of hypoglycemia exists unless the drug is combined with secretagogues (consider initial reduction in secretagogue). There is a minor increase in hypoglycemia risk if the drug is combined with TZDs.

• Moderate weight loss of about 10 pounds is seen after sustained use.

• A dose-limiting side effect is nausea. Approximately 50% of patients report some degree of nausea, but stop the drug secondary to the problem. This problem seems to lessen with time.

• Patients should decrease meal size and carbohydrate content of meals prior to use of exenatide to lessen problem of nausea.

• Dose should be given 10-15 minutes prior to the two largest meals of the day, which should be spaced at least 6 hours apart.

• Drugs can be stored at room temperature for 30 days after first dose is given.

• Drugs can be combined with sulfonylurea, metformin, sulfonylurea + metformin, TZDs, or metformin + TZD. Currently, they are not indicated in combination with insulin.

• Begin with 5 mcg injected bid for 1 month; then increase to 10 mcg bid as tolerated secondary to GI toxicity.

• Drugs are supplied as a pen device that contains 60 doses (1-month supply).

• They are most effective in lowering postprandial glucose elevations.

• Recent reports suggest a possible risk for pancreatitis associated with use of GLP agonists; however, whether the relationship is causal or coincidental is not yet clear.

A1c reduction

A reduction of 0.5-1.0% is expected.


The monthly cost is approximately $150-200.

[Table 13-7. Sample Titration Schedules for Basal and Prandial Insulin]

[Table 13-8. Insulin Products]

Cautions and contraindications

• Medication should not be given to patients with GFR ≤ 30 mL/min.

• It should not be given to patients with severe gastrointestinal disease, including gastroparesis.

• It should not be used in patients with DKA or type 1 DM.


Table 13-9 provides further dosing information.

Amylin mimetics

Mechanism of action

The medication is an analog of endogenous amylin that when dosed at therapeutic levels causes (1) decreased production of glucagon, (2) slowing of

[Table 13-9. Incretin Mimetics]

gastric emptying, and (3) increased satiety and weight loss.

Clinical considerations

• Drug can be used in combination with insulin therapy in both type 1 and type 2 DM patients who have failed to achieve desired glucose control.

• Because of significant risk of severe hypoglycemia, prandial insulin dose should be decreased by 50% when starting pramlintide.

• A dose-limiting side effect is nausea, which seems to lessen over time.

• For type 2 DM, start with 60 mcg (10 units) before meals; increase to 120 mcg before meals when no significant nausea has occurred for 3-7 days.

• For type 1 DM, start with 15 mcg (2.5 units) before meals; increase to 30 to 60 mcg before meals when no significant nausea has occurred for 3-7 days.

• Opened vials may be stored at room temperature for 28 days.

A1c reduction

A reduction of 0.5-1.0% is expected.


The cost per month is about $100-300.

Cautions and contraindications

The medication should not be used in patients with

• Severe gastrointestinal disease, including gastroparesis

• Poor adherence with current insulin regimen or self-monitoring of blood glucose

• Recurrent severe hypoglycemia requiring assistance in the past 6 months

• A1c ≥ 9%

• Hypoglycemia unawareness


Table 13-10 provides further dosing information.

13-3. Nondrug Therapy


Weight loss is recommended for all diabetics who are overweight or obese. Modest weight loss (5%) has been shown to decrease insulin resistance in type 2 diabetes.

Lifestyle changes through diet and exercise should be emphasized. Patient education is an essential component of successful diabetes management.

Medical Nutrition Therapy

Medical nutrition therapy (MNT) should be individualized to achieve treatment goals with consideration of usual dietary habits, metabolic profile, and lifestyle.

Carbohydrate (CHO) should be monitored by exchanges, carbohydrate counting, or experience-based estimation. CHO should be 45-60% of total daily caloric intake. If intensive insulin therapy is used with a premeal bolus dose of insulin, insulin should be adjusted to cover the daily CHO intake. With basal insulin therapy (when the premeal bolus is not used) or oral antidiabetic medications, the CHO intake must be adjusted so that it is consistent with the effects of therapy.

Protein should be 15-20% of total daily caloric intake. Protein intake should be modified if renal function is reduced. Saturated fat should be < 7% of total daily calories. Cholesterol should be < 200 mg/d.

Fiber intake should be encouraged, but there is no reason to recommend a greater amount than that recommended for persons without DM (14 g fiber/1,000 kcal).

Daily alcohol intake should be limited (adult females: one drink or fewer; adult males: two drinks or fewer).

Physical Activity and Exercise

Regular exercise improves blood glucose control, reduces cardiovascular risk factors, and contributes to

[Table 13-10. Amylin Mimetics]

weight loss. An exercise regimen should be individualized. The patient's preexercise program history and a detailed medical examination are essential.

For most patients, a program of 150 min/week of moderate-intensity aerobic exercise is recommended. The program should be adjusted in the presence of macro- and microvascular complications that may be worsened:

• Retinopathy: Vigorous exercise may be contraindicated because of the risk of triggering vitreous hemorrhage or retinal detachment.

• Peripheral neuropathy: Non-weight-bearing activities may be best because decreased pain sensation in the extremities increases the risk of skin breakdown and infection.

• Autonomic neuropathy: Patients should undergo cardiac investigation before increasing physical activity, which may lead to decreased cardiac responsiveness to exercise, postural hypotension, and so forth.

Blood glucose monitoring may be necessary before and after exercise. Fast-acting oral carbohydrates should be available during and after exercise.

Diabetes Self-Management Education

Diabetes self-management education (DSME) provides a means for persons with DM to become empowered and assist with self-care. Education content includes the disease process; acute and long-term complications; drug and nondrug treatments; monitoring; preventive measures; decision-making skills; specific self-care measures relative to foot, skin, dental, and eye care; goal setting; and psychosocial adjustment.

DSME should be offered in a variety of settings, typically by a multidisciplinary team.

13-4. Key Points

• DM is a group of chronic metabolic diseases exhibiting hyperglycemia resulting from defects in insulin secretion, action, or both.

• Type 1 diabetes results from immune-mediated β-cell destruction, which leads to absolute insulin deficiency.

• Type 2 diabetes is characterized by relative insulin deficiency, insulin resistance, or both.

• See

Table 13-11 for a comparison of type 1 and type 2 diabetes.

[Table 13-11. Comparison of Type 1 and Type 2 Diabetes Mellitus]

• The principal treatment goals include maintaining blood glucose levels in the normal or near-normal range and preventing acute and chronic complications.

• Goals of diabetes therapy include achieving and maintaining glycemic control and reaching recommended blood pressure and lipid goals.

• Outcomes of uncontrolled blood glucose include cardiovascular, kidney, eye, and nerve disease.

• Pharmacotherapy treatment of DM should be individualized to each patient considering such factors as glucose control goals; length of time with DM; concomitant diseases; psychosocial issues, including available support for the patient, patient motivation, medication and DM supply costs, and the level of risk for complications secondary to DM control.

• Multiple studies have shown improved glycemic control delays the onset of, slows the progression of, and lowers the risk of long-term microvascular complications.

• Combination therapy of two or more po therapies, po therapies plus insulin, or po products plus GLP-1 analogs will be required in most patients to maintain continued DM control.

• Metformin

• Is considered first-line therapy in newly diagnosed type 2 DM

• Is contraindicated in renal dysfunction patients

• Has low or minimal risk of hypoglycemia with monotherapy

• Has GI side effects (flatulence, GI upset, abdominal pain, diarrhea, bloating), which are dose-limiting problems

• Causes no weight gain

• May decrease the progression to DM in high-risk patients

• Secretagogues

• Are helpful in combination with other po agents and injectable products

• Increase risk of hypoglycemia (sulfonylureas > meglitinides)

• Increase weight (sulfonylureas > meglitinides)

• Have high rate of failure over time

• Must be used with caution in renally impaired and elderly patients

• Thiazolidinediones

• Help improve peripheral insulin resistance

• Increase weight and edema

• Have low or minimal risk of hypoglycemia with monotherapy

• Are contraindicated in patients with congestive heart failure

• Have delayed time to see full effects on DM control

• May decrease the progression to DM in high-risk patients

• Alpha-glucosidase inhibitors

• Block absorption of carbohydrates in the small intestine

• Have low or minimal risk of hypoglycemia with monotherapy

• Have GI side effects (flatulence, GI upset, abdominal pain, diarrhea, bloating), which are dose-limiting problems

• Are more effective for postprandial hyperglycemia

• Have minimal effect on weight

• GLP-1 and amylin-based medications

• Include Byetta (GLP-1 analog)

• Increase insulin production in a glucose-dependent fashion

• Decrease production of glucagon

• Improve β-cell functioning

• Slow gastric emptying

• Increase satiety and possible weight loss

• Have a dose-limiting side effect of nausea

• Are injectable products

• Are for use in type 2 DM

• Are high cost

• DPP-IV inhibitor (Januvia)

• Increases insulin production in a glucose-dependent fashion

• Decreases production of glucagon

• Improves β-cell functioning

• Has no effect on weight

• Is well tolerated with few side effects

• Is for use in type 2 DM

• Is high cost

• Amylin mimetic (Symlin)

• Decreases production of glucagons

• Slows gastric emptying

• Increases satiety and possible weight loss

• Has significant risk of hypoglycemia in combination with insulin in type 1 DM

• Has the dose-limiting side effect of nausea

• Is for use in type 1 and 2 DM

• Is high cost

• Insulin

• Is essential for type 1 DM

• Is often used in type 2 DM in combination with other therapies

• Should be considered initial agent if glucose is > 250 mg/dL or A1c > 10%

• Is often started as basal therapy (0.1-0.2 units/kg/d) added to an existing po regimen

• Should be individualized to the patient's goals and motivation: intensive insulin therapy (> 3 doses/d or use of continuous subcutaneous insulin infusion) is replacing conventional insulin therapy (split-mix dosing: two-thirds of total daily dose)

• Varies principally by source; appearance; time-activity profiles (onset, peak, and duration); dosing; and route of administration

• May have these adverse events: hypoglycemia, weight gain, and lipodystrophies

• Has the same mechanism of action for all types

• Patient education is essential for the management of DM because it provides a means for persons with this chronic disease to become empowered, cope effectively, and engage in appropriate self-care.

• Recommended lifestyle modifications include weight management, increased physical activity, and smoking cessation.

13-5. Questions

Use Patient Profile 1 to answer Questions 1-5.


Patient Name:

Barbara Evens



413 Summit Street






5' 5"



190 lb






African American



Penicillin, sulfa drugs




1) Type 2 DM



1) Hypertension


2) Asthma


Lab/Diagnostic Tests:











Serum K








Serum K








Serum creatinine








Serum K


Additional Orders:

1. Referral to dietitian for weight reduction diet

2. Low impact exercise 30 mins 3 days per week

Dietary Considerations:

1. Dietary changes per dietitian consult

2. Enteral and parenteral

Pharmacist Notes and Other Patient Information:







Advise patient to continue SMBG and to report any hypoglycemic episodes. Instructed patient to treat hypoglycemia with glucose or lactose products. Instructed patient to take acarbose with first bite of meal. Foot exam negative. Patient reports having 1-2 drinks of bourbon per day.



Informed patient to report any changes in BG.

Medication Orders:




Drug & strength







Propranolol 20 mg


1 PO bid





Albuterol inhaler


1-2 inhalations q4-6h





Acarbose 25 mg


1 tab PO w/meals





Acarbose 50 mg


1 tab PO w/meals





Prednisone 10 mg


1 tab PO daily





Propranolol 20 mg


1 tab PO bid





Albuterol inhaler


1-2 inhalations q4-6h





ASA 81 mg


1 tab PO daily



Chlorpropamide would be problematic in this case for which of the following reasons?

I. Alcohol intake

II. Sulfa allergy

III. Asthma

IV. Hypertension

V. Drug-drug interaction

A. I only

B. III only

C. I and II only

D. II, III, and IV

E. I, II, and V



Because of a renal protection mechanism, the drug class of choice for Ms. Even's hypertension is a(n)

A. β-blocker.

B. loop diuretic.

C. thiazide diuretic.

D. α-adrenergic blocker.

E. angiotensin-converting enzyme inhibitor.



One of the most common adverse drug events caused by Ms. Even's oral antidiabetic agent is

A. flatulence.

B. hypoglycemia.

C. renal failure.

D. hyperglycemia.

E. weight gain.



Which of the following medications on the medication list in this case can mask the symptoms of hypoglycemia?

A. Propranolol

B. Albuterol

C. Acarbose

D. Prednisone

E. Aspirin



What change in the following laboratory tests might be observed with the addition of prednisone to Ms. Even's drug regimen?

A. Increase in LFTs

B. Decrease in BUN

C. Decrease in serum creatinine

D. Increase in serum creatinine

E. Increase in blood glucose


Use Patient Profile 2 to answer questions 6-10.


Patient Name:

Tom Right



20 Blue Ridge Drive






5' 6"



135 lb













1) Type 2 DM

2) Epilepsy



1) Hypertension

2) Fungal infection under toenails


Pharmacist Notes and Other Patient Information:







Patient should be monitored closely for hypoglycemia. Teach patient signs and symptoms of hypoglycemia and treatment measures.

Medication Orders:




Drug & strength







Tolazamide 250 mg


1 tab PO daily





Glimepiride 2 mg


1 tab PO daily





Lisinopril 5 mg


1 tab PO daily





Phenytoin extended


300 mg PO daily







50 mg PO daily





Regular insulin


5 units SC before meals



What is the principal drug-related problem in this patient's medication record?

A. Insulin therapy not indicated for persons with type 2 DM

B. Therapeutic duplication of sulfonylurea therapy

C. Potential decrease of BG because of drug-drug interaction between phenytoin and tolazamide

D. Potential increase of BG because of drug-drug interaction between glimepiride and itraconazole

E. Use of an ACE inhibitor for hypertension in type 2 DM



All of the following monitoring parameters are necessary for Mr. Right except

A. periodic glycosylated hemoglobin A1c.

B. SMBG levels.

C. phenytoin levels.

D. blood pressure readings.

E. quarterly serum C-peptide level.



Which of the following is an inappropriate treatment for a mild hypoglycemic episode?

A. 1/2 cup of diet soda

B. 6-7 hard candies containing sugar

C. 3 glucose tablets

D. 1/2 cup of regular soda

E. 5 small sugar cubes



Persons on insulin therapy should be advised to rotate their injection sites for which of the following reasons?

A. It reduces the risk of infection.

B. It reduces the risk of lipoatrophy.

C. It reduces the risk of lipohypertrophy.

D. It reduces the risk of generalized myalgia.

E. This advice is outdated because of the use of human insulin.



Which of the following is the most appropriate treatment for a severe hypoglycemic episode?

A. 1/2 cup of diet soda

B. 3 hard candies containing sugar

C. 1 glucose tablet

D. Glucagon injection

E. 2-3 small sugar cubes



Commercially available insulin (as of May 2005) may be administered by which of the following routes?

I. Intravenously

II. Subcutaneously

III. Via inhalation

IV. Transdermally

V. Sublingually

A. I only

B. II only

C. I and II only

D. II, III, and IV

E. I, II, and V



Insulin therapy is indicated in all of the following except

A. newly diagnosed type 1 DM.

B. gestational diabetes mellitus not controlled by diet.

C. hyperglycemic hyperosmolar nonketotic syndrome (HHNS).

D. newly diagnosed type 2 DM.

E. diabetic ketoacidosis (DKA).



Insulin dosing is adjusted on the basis of the following parameters:

I. Liver function test results

II. Dietary intake

III. Physical activity and exercise

IV. Blood glucose levels

V. Ophthalmic examinations

A. I only

B. II only

C. I and II only

D. II, III, and IV

E. I, II, and V



Which of the following oral antidiabetic agents is a micronized formulation?

A. Micronase

B. Glynase

C. Glucotrol XL

D. Amaryl

E. Orinase



Insulin that has been stored in a refrigerator should be allowed to reach room temperature prior to administration to

A. allow for proper mixing.

B. minimize painful injections.

C. prevent frosting or clumping.

D. delay systemic absorption.

E. prevent change in clarity.



When mixing rapid- or short-acting insulin with intermediate- or long-acting insulin, which of the following insulins should be drawn up first?

A. Regular


C. Lente

D. Ultralente

E. Glargine



Uniform dispersion of insulin suspensions can be obtained by

A. vigorously shaking the vial.

B. rolling the vial gently between the hands.

C. warming the vial in a microwave.

D. packing the vial in dry ice.

E. keeping the vial at room temperature (68-75°F).



Of the following types of insulin, which can be administered intravenously?

A. Glargine

B. Lente

C. Regular

D. Ultralente




Diabetes mellitus is the leading cause of which of the following complications?

A. Pancreatitis

B. Fatty liver

C. Blindness

D. Stroke

E. Deafness



Which of the following is an indication that a patient is developing a long-term complication from diabetes mellitus?

A. Tachycardia

B. Glucosuria

C. Leukocytosis

D. Proteinuria

E. Tinnitus



Which sulfonylurea has been associated with the greatest incidence of prolonged hypoglycemia in the elderly?

A. Tolazamide

B. Tolbutamide

C. Chlorpropamide

D. Glimepiride

E. Glipizide



Which of the following drugs taken with alcohol is most likely to cause a disulfiram-like reaction?

A. Chlorpropamide

B. Acarbose

C. NPH insulin

D. Glucagon

E. Pioglitazone



Metformin should be withheld for 48 hours prior to any procedure requiring the use of parenteral iodinated contrast medium because of the potential for this adverse drug event:

A. Optic neuritis

B. Metabolic alkalosis

C. Lactic acidosis

D. Purple-toe syndrome

E. Tinnitus



The use of insulin in a woman with GDM helps reduce the incidence of which complication in the fetus?

A. Macrosomia

B. Cystic fibrosis

C. Deafness

D. "Soft bones"

E. Eczema



Metformin would not be an option for a patient with which of the following diagnoses?

A. Iron deficiency anemia

B. Impaired renal function

C. Hypertension

D. Type 2 DM

E. Frequent hypoglycemic episodes



Nocturnal hypoglycemia resulting in rebound hyperglycemia in type 1 DM is termed

A. honeymoon period.

B. Somogyi effect.

C. dawn phenomenon.

D. hyperglycemic phase.

E. insulin resistance syndrome.



Which of the following is a potentially fatal adverse drug event of Glucophage?

A. Weight gain

B. Frequent urination

C. Diarrhea

D. Lactic acidosis

E. Angioedema



All of the following are true of acarbose therapy except

A. it is contraindicated in inflammatory bowel disease.

B. it should be taken with the first bite of each meal.

C. it does not cause hypoglycemia or weight gain.

D. hypoglycemia attributable to combination therapy should be treated with sucrose.

E. LFTs are given every 3 months during the first year and periodically thereafter (if the dose is > 50 mg tid).



Prandin is a nonsulfonylurea secretagogue. Adverse drug events include all of the following except

A. upper respiratory infection.

B. arthropathy.

C. hypoglycemia.

D. back pain.

E. hyperglycemia.



Patient counseling relative to meglitinides should include the following points:

I. It must be taken 30 minutes before main meals.

II. If a meal is omitted, do not take.

III. It enhances preprandial glucose utilization.

IV. Hyperglycemia is a potential adverse drug event.

V. Disulfiram-like reaction is possible when ingested with ETOH.

A. I only

B. III only

C. I and II only

D. II, III, and IV

E. I, II, and V



Which one of the following antidiabetic agents does not require liver function tests for monitoring?

A. Glargine

B. Miglitol

C. Rosiglitazone

D. Acarbose

E. Metformin



Adverse drug events reported for pioglitazone (Actos), a thiazolidinedione, include all of the following except

A. exacerbation of congestive heart failure.

B. resumption of ovulation.

C. edema.

D. upper respiratory infection.

E. megaloblastic anemia.



All of the following drugs have a direct glucogenic effect except

A. thiazide diuretics.

B. corticosteroids.

C. nicotinic acid.

D. sympathomimetics.

E. acetohexamide.



Which of the following is the mechanism of action for the sulfonylureas?

A. They stimulate pancreatic β-cells to secrete insulin.

B. They delay carbohydrate metabolism and absorption (owing to inhibition of intestinal and pancreatic enzymes).

C. They increase hepatic insulin sensitivity and decrease hepatic glucose production.

D. They increase skeletal muscle and adipose tissue insulin sensitivity and decrease hepatic glucose production.

E. They decrease blood glucose and assist with blood glucose control by increasing glucose uptake and use by peripheral tissues.



All of the following are signs or symptoms of hypoglycemia except

A. tachycardia.

B. diaphoresis.

C. shakiness.

D. polyuria.

E. pallor.



Pramlintide (Symlin)

A. is a basal insulin.

B. is an insulin analog.

C. is an oral insulin.

D. is an inhaled insulin.

E. is an injectable synthetic version of the human hormone amylin.


13-6. Answers


E. Chlorpropamide is contraindicated in persons with a sulfa allergy. Alcohol (ETOH) ingestion with chlorpropamide could lead to a disulfiram-like reaction. Also, acute ingestion of ETOH (especially in the fasting state) includes the risk of severe hypoglycemia. Chlorpropamide and prednisone may produce a drug-drug interaction resulting in hyperglycemia. Items III and IV are nonproblematic in this case in relation to chlorpropamide.



E. Angiotensin-converting enzyme inhibitors exhibit a renal protective mechanism in people with DM. None of the remaining drugs exhibits such an effect.



A. The most common adverse drug events for acarbose are flatulence, abdominal pain, and diarrhea. These adverse effects may be decreased by titrating the dose gradually and taking the drug with the first bite of each meal. There may also be an increase in LFTs.



A. Propranolol (a nonselective β-blocker) can mask the symptoms of hypoglycemia (i.e., tachycardia [palpitations], pallor, shakiness [tremor], paresthesia, hunger, diaphoresis [sweating], dizziness, and blurred vision). None of the remaining drugs listed has this effect.



E. The increase in LFTs may be due to acarbose, and the increase in serum creatinine may represent the development or progression of nephropathy, a long-term complication of DM. The decrease in the serum creatinine and BUN (blood urea nitrogen) are incorrect answers. Prednisone, a corticosteroid, has a dose-dependent, direct glucogenic and glycosuric effect, and therefore an increase in blood glucose (BG) might be observed.



B. Although tolazamide and glimepiride are first- and second-generation sulfonylureas, duplication of drug class is inappropriate. These agents are both intermediate acting and therefore might potentiate the adverse drug event of hypoglycemia. Insulin may be indicated in a person with type 2 DM as the disease progresses. The potential drug-drug interaction between phenytoin and tolazamide could result in an increased BG (blood glucose) level, and the potential drug-drug interaction between glimepiride and itraconazole could result in a decreased BG level. An ACE inhibitor for hypertension in type 2 DM is appropriate because this drug is renal protective.



E. The A1c and self-monitoring of blood glucose (SMBG) tests are essential for monitoring the success of glucose control therapy. The SMBG gives an immediate determination of BG level, and the A1c gives an average reading over the previous 2-3 months (or 120 days, the lifespan of a red blood cell). Phenytoin levels are necessary for monitoring therapeutically appropriate levels, and blood pressure readings are necessary for monitoring the success of antihypertensive therapy. A serum C-peptide might be diagnostic for the determination of functioning β-cells; however, if performed, it is done very infrequently to reduce cost.



A. One-half cup of diet soda would be inappropriate because a mild hypoglycemic episode requires a fast-acting oral carbohydrate for resolution and diet soda has none. The other options would all be appropriate for resolution of the event.



C. Lipohypertrophy (a bulging of the injection site) is due to nonrotation of injection sites. The risk of infection may be reduced by using aseptic injecting technique. Lipoatrophy (a pitting of the injection site) may be due to an antigenic response to insulin. The advice regarding rotation of injection site is not outdated.



D. Glucagon, a pancreatic hormone that is given parenterally, is the most appropriate treatment for a severe hypoglycemic episode (life threatening), because the patient may be unconscious and not able to take a fast-acting carbohydrate by mouth. The other items represent inappropriate treatment for mild to moderate hypoglycemia (the amounts of items B, C, and E are inadequate, and the soda in item A should be regular soda).



C. Pharmaceutical research has developed inhaled insulin products that are still being tested. At present, the commercially available insulins may be administered only intravenously or subcutaneously. A previously available inhaled insulin product, Exubra, was voluntarily withdrawn from the market by the manufacturer.



D. Newly diagnosed type 2 DM should first have a trial with MNT and exercise, and if this nondrug therapy fails, oral antidiabetic monotherapy should be added. Combination oral therapy would be indicated next with failure of monotherapy. Then, following the failure of oral therapy, insulin monotherapy or insulin therapy in combination with oral agents is indicated. Insulin is indicated in all the other situations.



D. Dietary intake, physical activity and exercise, and blood glucose levels are the parameters used in adjusting insulin dosing (e.g., if the parameters of dietary intake and blood glucose levels are decreased and if physical activity and exercise are increased, the insulin dosing would require reduction to avoid hypoglycemia). Monitoring of these parameters is critical to adjusting the insulin regimen. Items I and V are incorrect.



B. Glynase is a micronized formulation of glyburide that is significantly absorbed (e.g., a 3 mg tablet provides blood levels similar to a 5 mg conventional tablet). Micronase is a trade name for nonmicronized glyburide. Glucotrol XL is the name of an extended formulation of glipizide. Orinase is the trade name for tolbutamide (the only first-generation sulfonylurea listed here), and Amaryl is the trade name for glimepiride.



B. Refrigerated insulin is allowed to reach room temperature prior to administration to minimize painful injections. Proper mixing, prevention of frosting or clumping, or maintenance of clarity have nothing to do with reaching room temperature. Systemic absorption would actually be enhanced by increasing to room temperature, not delayed.



A. Regular or clear insulin is always drawn up first to ensure that all persons mixing insulins will use the same procedure and that no intermediate- or long-acting insulin will be placed in the regular insulin vial, potentially causing contamination and dose variance. Glargine is also a clear insulin; however, it is never to be mixed with other insulins because of the low pH (4.0) of its diluents.



B. Uniform dispersion of insulin suspensions can be obtained by gently rolling the vial between the hands. Insulin is a fragile molecule, and all the other means listed could cause molecular degradation.



C. Of these insulins, regular is the only one that can be administered intravenously. Although glargine is clear like regular insulin, its pH is 4.0, and it should never be given intravenously. The remaining insulins are suspensions and also should never be given intravenously.



C. DM is the leading cause of new cases of blindness among adults 20-74 years of age in the United States. There is also an increased incidence of stroke with DM, but DM is not the leading cause of this problem. The other items are incorrect.



D. Proteinuria is an indication that a patient is developing the long-term complication of nephropathy. Items A, B, and C could be related to acute complications such as DKA (glucosuria and leukocytosis) and hypoglycemia (tachycardia). Item E is incorrect.



C. Chlorpropamide has a t1/2 of 35 hours and a duration of action of 60 hours; therefore, it has been associated with prolonged hypoglycemia in the elderly (perhaps because of their declining renal function). The other sulfonylureas have reported less hypoglycemia.



A. Chlorpropamide has had the greatest reporting of this drug interaction relative to the first-generation sulfonylureas. The remaining drugs listed have not had reports of this adverse drug event.



C. Lactic acidosis can result if metformin (Glucophage) is given in this situation, and it can be potentially fatal. Renal function must be evaluated following such a procedure, and it must be normal before metformin may be resumed. The other items are incorrect.



A. Macrosomia (abnormally large fetal body size) is one of the fetal complications of concern in GDM. The primary benefit of insulin therapy is reduction in the incidence of macrosomia. The other items are incorrect.



B. Contraindications for metformin are renal dysfunction for those predisposed to lactic acidosis. Metformin does not cause hypoglycemia, and it is indicated in type 2 DM. Hypertension and iron deficiency anemia are incorrect answers. Metformin may cause megaloblastic anemia.



B. The Somogyi effect is rebound hyperglycemia or early morning hyperglycemia secondary to nocturnal hypoglycemia. The person with type 1 DM may experience a honeymoon period—a phase of erratic insulin secretion during destruction of β-cells by islet cell antibodies. This short-lived remission lasts months to a year. The dawn phenomenon is fasting hyperglycemia (prebreak-fast) caused by decreased plasma insulin during the night or the anti-insulin effect of nocturnal growth hormone. Items D and E are incorrect.



D. Lactic acidosis is a potentially fatal adverse drug event of Glucophage (metformin). It does not cause weight gain. Modest weight loss is possible, and no hypoglycemia is reported when metformin is used as monotherapy. Diarrhea is an adverse drug event, but with gradual dose titration and administration with food, it decreases over time. Items B and E are incorrect.



D. Oral glucose instead of carbohydrate sources with sucrose (cane sugar) or fructose is used because absorption of these is inhibited. The remaining items are true of acarbose therapy.



E. Prandin may cause hypoglycemia like the sulfonylureas. Hyperglycemia is not one of the adverse drug events reported. Prandin may cause all the other adverse drug events.



C. Meglitinides should be taken 30 minutes before main meals, and if a meal is omitted, the drug should not be taken. It enhances postprandial glucose utilization; hypoglycemia, not hyperglycemia, may occur; and disulfiram-like reactions are not reported.



A. The α-glucosidase inhibitors (e.g., acarbose), biguanides (e.g., metformin), and thiazolidinediones (e.g., rosiglitazone) all require LFTs for monitoring. Glargine, a long-acting insulin, does not require LFTs for monitoring; rather it requires blood glucose monitoring.



E. Megaloblastic anemia is a reported adverse drug effect for metformin, but not for Actos. All the other items listed are reported adverse drug effects. Since troglitazone (Rezulin), a thiazolidinedione, was withdrawn from the market in 2000 because of severe liver toxicity, this adverse drug effect could potentially occur with Actos; therefore, LFTs should be performed periodically.



E. Acetohexamide has a hypoglycemic effect. All the other drugs listed have a direct glucogenic effect.



A. The sulfonylureas stimulate pancreatic β-cells to secrete insulin. Item B is the mechanism of action for α-glucosidase inhibitors, item C is the mechanism of action for the biguanide metformin, item D is the mechanism of action for the glitizones, and item E is the mechanism of action for insulin.



D. Polyuria (excessive urination) is one of the classic signs and symptoms of DM. All of the other answers listed are some of the signs and symptoms of hypoglycemia, which can be life threatening.



E. Pramlintide (Symlin) was approved in March 2005 as the first new type 1 diabetes treatment in more than 80 years. It is an injectable synthetic version of the human hormone amylin.


13-7. References

American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes Care. 2009: 32(suppl 1):S13-61.

Bode BW, ed. Medical Management of Type 1 Diabetes. Alexandria, Va. American Diabetes Association; 2008.

Burant CF, ed. Medical Management of Type 2 Diabetes. Alexandria, Va. American Diabetes Association; 2008.

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-97.

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160-67.

Funnell MM, Brown TL, Childs BP, et al. National Standards for Diabetes Self-Management Education. Diabetes Care. 2007;30:1630-7.

Diabetes Control and Complications Trial Research Group. The effect of intensive treatment on the development and the progress of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-86. Available at:

Setter SM, White JR Jr, Campbell RK. Diabetes. In: Helms RA, Quan DJ, Herfindal ET, Gourley DR, eds. Textbook of Therapeutics. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2006:1042-105.

Stoneking K, Farr G. Early use of insulin in type 2 diabetes. Drug Topics October 2, 2002. Available at:

Triplett CL, Reasner CA, Isley WL. Diabetes mellitus. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:1205-41.

UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-65.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risks of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-53.

University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult onset diabetes. Diabetes. 1970;19(suppl 2):1-26.

White JR, Campbell RK. Drug/drug and drug/disease interactions and diabetes. Diabetes Educator. 1995;21:283-9.