A 66-year-old woman was prompted by her dentist to seek medical attention for an unusually enlarged, smooth-appearing tongue (Figure 1). She also complained of fatigue, dyspnea on exertion, and tingling of her hands.

Basic laboratory tests showed normocytic anemia and renal insufficiency. Her thyrotropin level was within normal limits. Serum protein electrophoresis showed a monoclonal M-spike, which prompted a bone marrow biopsy that was diagnostic of multiple myeloma.

Transthoracic echocardiography revealed diffuse hypokinesis with a restrictive filling pattern, myocardial thickening, and moderate mitral and tricuspid regurgitation, highly suggestive of an infiltrative cardiomyopathy. Biopsy of the right ventricle confirmed cardiac amyloidosis of the amyloid immunoglobulin light chain (AL) subtype.

The patient underwent chemotherapy, followed by autologous stem-cell transplantation. She achieved successful remission, and her cardiomyopathy was compensated.

AMYLOIDOSIS IS HETEROGENEOUS

Amyloidosis is a heterogeneous syndrome characterized by abnormal folding of proteins that deposit as insoluble fibrils in different tissues, impairing both structure and function. Virchow was the first to describe amyloid (from amylon, Greek for starch) as an abnormal material seen in postmortem examination of the liver. On Congo red staining, the extracellular proteins appear as salmon-red conglomerates, which also show apple-green birefringence under polarized light.

Amyloidosis can be localized but more often represents a systemic process, often associated with a plasma cell dyscrasia such as multiple myeloma.

Modern classification is based on the precursor protein,¹ eg:

• Light chains (AL)
• Acute-phase protein (AA)
• Beta-2-microglobulin (Aß2M)
• Transthyretin (ATTR; occurring in senile systemic amyloidosis)
• Other proteins (occurring in various forms of hereditary systemic amyloidosis).

AMYLOIDOSIS AND THE TONGUE

Macroglossia is defined as protrusion of the tongue beyond the alveolar ridge of the teeth at rest. When caused by amyloidosis, it is most often associated with the systemic AL variant and is present in 10% to 23% of patients with this subtype.²

On physical examination, tongue enlargement can present with lateral indentations, with a smooth contour or with nodular deposits. Less often, bullous lesions, vesicles, and ulcers can also be seen, particularly on the lips. Infiltration of salivary glands can result in xerostomia. Functional symptoms, such as hypogeusia, dysarthria, dysphagia, dysphonia, and, in advanced cases, upper-airway dysfunction can result from restricted mobility of the tongue and tethering to deeper structures.

Surgical management may be necessary if severe obstructive symptoms are present, but infiltrative lesions tend to recur.

AMYLOIDOSIS AND THE HEART

Cardiac involvement in amyloidosis is currently the primary determinant of prognosis.³ It is more often seen in the AL, senile, and hereditary forms. It usually manifests as diastolic heart failure, but angina, orthostatic hypotension, dysrhythmias, and syncope can also occur. Systolic dysfunction is typically a late finding in the course of the disease.

Although an electrocardiographic pattern of low voltage in the precordial and limb leads has been classically associated with cardiac amyloidosis, only 30% of patients with the senile and hereditary forms show this feature.⁴ Left ventricular hypertrophy on electrocardiography is thought to be uncommon, but it has been reported in 16% of patients with AL amyloidosis and biopsy-proven cardiac involvement.⁵ Cardiac troponin levels can be elevated, as seen in other infiltrative cardiomyopathies.³ The diagnosis can be established by endomyocardial biopsy or indirectly by cardiac imaging and a positive extracardiac biopsy.

Drug therapy is supportive and mainly involves diuretics, since angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers may cause hypotension and exacerbate myocardial dysfunction. The specific treatment varies depending on the underlying cause of amyloidosis.

A 66-year-old woman was prompted by her dentist to seek medical attention for an unusually enlarged, smooth-appearing tongue (Figure 1). She also complained of fatigue, dyspnea on exertion, and tingling of her hands.

Basic laboratory tests showed normocytic anemia and renal insufficiency. Her thyrotropin level was within normal limits. Serum protein electrophoresis showed a monoclonal M-spike, which prompted a bone marrow biopsy that was diagnostic of multiple myeloma.

Transthoracic echocardiography revealed diffuse hypokinesis with a restrictive filling pattern, myocardial thickening, and moderate mitral and tricuspid regurgitation, highly suggestive of an infiltrative cardiomyopathy. Biopsy of the right ventricle confirmed cardiac amyloidosis of the amyloid immunoglobulin light chain (AL) subtype.

The patient underwent chemotherapy, followed by autologous stem-cell transplantation. She achieved successful remission, and her cardiomyopathy was compensated.

AMYLOIDOSIS IS HETEROGENEOUS

Amyloidosis is a heterogeneous syndrome characterized by abnormal folding of proteins that deposit as insoluble fibrils in different tissues, impairing both structure and function. Virchow was the first to describe amyloid (from amylon, Greek for starch) as an abnormal material seen in postmortem examination of the liver. On Congo red staining, the extracellular proteins appear as salmon-red conglomerates, which also show apple-green birefringence under polarized light.

Amyloidosis can be localized but more often represents a systemic process, often associated with a plasma cell dyscrasia such as multiple myeloma.

Modern classification is based on the precursor protein,¹ eg:

• Light chains (AL)
• Acute-phase protein (AA)
• Beta-2-microglobulin (Aß2M)
• Transthyretin (ATTR; occurring in senile systemic amyloidosis)
• Other proteins (occurring in various forms of hereditary systemic amyloidosis).

AMYLOIDOSIS AND THE TONGUE

Macroglossia is defined as protrusion of the tongue beyond the alveolar ridge of the teeth at rest. When caused by amyloidosis, it is most often associated with the systemic AL variant and is present in 10% to 23% of patients with this subtype.²

On physical examination, tongue enlargement can present with lateral indentations, with a smooth contour or with nodular deposits. Less often, bullous lesions, vesicles, and ulcers can also be seen, particularly on the lips. Infiltration of salivary glands can result in xerostomia. Functional symptoms, such as hypogeusia, dysarthria, dysphagia, dysphonia, and, in advanced cases, upper-airway dysfunction can result from restricted mobility of the tongue and tethering to deeper structures.

Surgical management may be necessary if severe obstructive symptoms are present, but infiltrative lesions tend to recur.

AMYLOIDOSIS AND THE HEART

Cardiac involvement in amyloidosis is currently the primary determinant of prognosis.³ It is more often seen in the AL, senile, and hereditary forms. It usually manifests as diastolic heart failure, but angina, orthostatic hypotension, dysrhythmias, and syncope can also occur. Systolic dysfunction is typically a late finding in the course of the disease.

Although an electrocardiographic pattern of low voltage in the precordial and limb leads has been classically associated with cardiac amyloidosis, only 30% of patients with the senile and hereditary forms show this feature.⁴ Left ventricular hypertrophy on electrocardiography is thought to be uncommon, but it has been reported in 16% of patients with AL amyloidosis and biopsy-proven cardiac involvement.⁵ Cardiac troponin levels can be elevated, as seen in other infiltrative cardiomyopathies.³ The diagnosis can be established by endomyocardial biopsy or indirectly by cardiac imaging and a positive extracardiac biopsy.

Drug therapy is supportive and mainly involves diuretics, since angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers may cause hypotension and exacerbate myocardial dysfunction. The specific treatment varies depending on the underlying cause of amyloidosis.

A 66-year-old woman was prompted by her dentist to seek medical attention for an unusually enlarged, smooth-appearing tongue (Figure 1). She also complained of fatigue, dyspnea on exertion, and tingling of her hands.

Basic laboratory tests showed normocytic anemia and renal insufficiency. Her thyrotropin level was within normal limits. Serum protein electrophoresis showed a monoclonal M-spike, which prompted a bone marrow biopsy that was diagnostic of multiple myeloma.

Transthoracic echocardiography revealed diffuse hypokinesis with a restrictive filling pattern, myocardial thickening, and moderate mitral and tricuspid regurgitation, highly suggestive of an infiltrative cardiomyopathy. Biopsy of the right ventricle confirmed cardiac amyloidosis of the amyloid immunoglobulin light chain (AL) subtype.

The patient underwent chemotherapy, followed by autologous stem-cell transplantation. She achieved successful remission, and her cardiomyopathy was compensated.

AMYLOIDOSIS IS HETEROGENEOUS

Amyloidosis is a heterogeneous syndrome characterized by abnormal folding of proteins that deposit as insoluble fibrils in different tissues, impairing both structure and function. Virchow was the first to describe amyloid (from amylon, Greek for starch) as an abnormal material seen in postmortem examination of the liver. On Congo red staining, the extracellular proteins appear as salmon-red conglomerates, which also show apple-green birefringence under polarized light.

Amyloidosis can be localized but more often represents a systemic process, often associated with a plasma cell dyscrasia such as multiple myeloma.

Modern classification is based on the precursor protein,¹ eg:

• Light chains (AL)
• Acute-phase protein (AA)
• Beta-2-microglobulin (Aß2M)
• Transthyretin (ATTR; occurring in senile systemic amyloidosis)
• Other proteins (occurring in various forms of hereditary systemic amyloidosis).

AMYLOIDOSIS AND THE TONGUE

Macroglossia is defined as protrusion of the tongue beyond the alveolar ridge of the teeth at rest. When caused by amyloidosis, it is most often associated with the systemic AL variant and is present in 10% to 23% of patients with this subtype.²

On physical examination, tongue enlargement can present with lateral indentations, with a smooth contour or with nodular deposits. Less often, bullous lesions, vesicles, and ulcers can also be seen, particularly on the lips. Infiltration of salivary glands can result in xerostomia. Functional symptoms, such as hypogeusia, dysarthria, dysphagia, dysphonia, and, in advanced cases, upper-airway dysfunction can result from restricted mobility of the tongue and tethering to deeper structures.

Surgical management may be necessary if severe obstructive symptoms are present, but infiltrative lesions tend to recur.

AMYLOIDOSIS AND THE HEART

Cardiac involvement in amyloidosis is currently the primary determinant of prognosis.³ It is more often seen in the AL, senile, and hereditary forms. It usually manifests as diastolic heart failure, but angina, orthostatic hypotension, dysrhythmias, and syncope can also occur. Systolic dysfunction is typically a late finding in the course of the disease.

Although an electrocardiographic pattern of low voltage in the precordial and limb leads has been classically associated with cardiac amyloidosis, only 30% of patients with the senile and hereditary forms show this feature.⁴ Left ventricular hypertrophy on electrocardiography is thought to be uncommon, but it has been reported in 16% of patients with AL amyloidosis and biopsy-proven cardiac involvement.⁵ Cardiac troponin levels can be elevated, as seen in other infiltrative cardiomyopathies.³ The diagnosis can be established by endomyocardial biopsy or indirectly by cardiac imaging and a positive extracardiac biopsy.

Drug therapy is supportive and mainly involves diuretics, since angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers may cause hypotension and exacerbate myocardial dysfunction. The specific treatment varies depending on the underlying cause of amyloidosis.

A 71-year-old woman came to the hospital because of generalized weakness, fatigue, and exertional dyspnea.

She had a history of anemia, recurrent urinary tract infections, and hyperactive bladder. She had been taking nitrofurantoin for a urinary tract infection and phenazopyridine for dysuria, and she noticed that her urine was dark-colored.

She was of northern European descent. She was unaware of any family history of blood-related disorders. She had been admitted to the hospital 6 weeks earlier for symptomatic anemia after taking nitrofurantoin for a urinary tract infection. At that time, she received 2 units of packed red blood cells and then was discharged. Follow-up blood work done 2 weeks later—including a glucose-6 phosphate dehydrogenase (G6PD) assay—was normal.

On physical examination, she was pale and weak. Her hemoglobin level was 5.5 g/dL (reference range 14.0–17.5), with normal white blood cell and platelet counts and an elevated reticulocyte count. A comprehensive metabolic panel showed elevated indirect bilirubin and lactate dehydrogenase levels. A direct Coombs test for autoimmune hemolytic anemia was negative, as was a haptoglobin assay to look for intravascular hemolytic anemia. G6PD levels were normal, yet a peripheral blood smear (Figure 1) showed features of G6PD deficiency.

What was the cause of her anemia?

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

G6PD deficiency is an X-linked disorder¹ that can present as hemolytic anemia. Symptoms of hemolysis can range from mild to severe on exposure to an inciting agent. Men are more commonly affected than women, and affected women are mostly heterozygous. The severity of hemolysis in heterozygous women depends on inactivation of the unaffected X chromosome in some cells.

When exposed to oxidizing agents, people with G6PD deficiency do not have enough nicotinamide adenine dinucleotide phosphate to protect red blood cells.² This leads to oxidative denaturation of hemoglobin, formation of methemoglobin, and denaturation of globulin. These products are insoluble; they collect in red blood cells and are called Heinz bodies.³ When red blood cells containing Heinz bodies pass through the liver and spleen, the insoluble masses are taken up by macrophages, causing hemolysis and the formation of “bite cells”⁴ (so named because macrophages “bite” the Heinz bodies out of the red blood cells).

Patients with G6PD deficiency have all the clinical features of hemolytic anemia. On laboratory testing, the Coombs test is negative, the G6PD level is low, and the peripheral smear shows bite cells. The G6PD level is falsely normal or elevated during acute hemolysis because red blood cells deficient in G6PD are removed from circulation and replaced by young red blood cells. The G6PD level is also elevated after blood transfusion. Thus, the G6PD level should be tested 3 months after an acute event.

Hemolysis in G6PD is usually intermittent and self-limited. No treatment is needed except for avoidance of triggers and transfusion for symptomatic anemia. Of note, triggers include some of the drugs commonly used for urinary tract infections (sulfa drugs, nitrofurantoin, phenazopyridine) and antimalarials. Fava beans are also known to cause hemolytic crisis. A complete list of things to avoid can be found at www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISS-it.

There is no commercially available genetic testing kit for G6PD deficiency. Mutation analysis and G6PD gene sequencing are possible but are neither routinely done nor widely available.

BACK TO OUR PATIENT

Our patient’s hemolytic anemia was most likely drug-induced, secondary to a relative deficiency of G6PD. She had been taking nitrofurantoin and phenazopyridine; both of these are oxidizing agents and are known to cause acute hemolytic anemia in people with G6PD deficiency. The G6PD level can be normal after a recent blood transfusion and, as in our patient, during an acute episode of hemolysis.

Because of the strong suspicion of G6PD deficiency, both drugs were stopped when the patient was discharged from the hospital. She did not take either drug for 3 months. Her G6PD level was then retested and was found to be low, confirming the diagnosis. The patient was then advised not to take those drugs again. Since then, her hemoglobin level has remained stable and she has not needed any more blood transfusions.

A 71-year-old woman came to the hospital because of generalized weakness, fatigue, and exertional dyspnea.

She had a history of anemia, recurrent urinary tract infections, and hyperactive bladder. She had been taking nitrofurantoin for a urinary tract infection and phenazopyridine for dysuria, and she noticed that her urine was dark-colored.

She was of northern European descent. She was unaware of any family history of blood-related disorders. She had been admitted to the hospital 6 weeks earlier for symptomatic anemia after taking nitrofurantoin for a urinary tract infection. At that time, she received 2 units of packed red blood cells and then was discharged. Follow-up blood work done 2 weeks later—including a glucose-6 phosphate dehydrogenase (G6PD) assay—was normal.

On physical examination, she was pale and weak. Her hemoglobin level was 5.5 g/dL (reference range 14.0–17.5), with normal white blood cell and platelet counts and an elevated reticulocyte count. A comprehensive metabolic panel showed elevated indirect bilirubin and lactate dehydrogenase levels. A direct Coombs test for autoimmune hemolytic anemia was negative, as was a haptoglobin assay to look for intravascular hemolytic anemia. G6PD levels were normal, yet a peripheral blood smear (Figure 1) showed features of G6PD deficiency.

What was the cause of her anemia?

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

G6PD deficiency is an X-linked disorder¹ that can present as hemolytic anemia. Symptoms of hemolysis can range from mild to severe on exposure to an inciting agent. Men are more commonly affected than women, and affected women are mostly heterozygous. The severity of hemolysis in heterozygous women depends on inactivation of the unaffected X chromosome in some cells.

When exposed to oxidizing agents, people with G6PD deficiency do not have enough nicotinamide adenine dinucleotide phosphate to protect red blood cells.² This leads to oxidative denaturation of hemoglobin, formation of methemoglobin, and denaturation of globulin. These products are insoluble; they collect in red blood cells and are called Heinz bodies.³ When red blood cells containing Heinz bodies pass through the liver and spleen, the insoluble masses are taken up by macrophages, causing hemolysis and the formation of “bite cells”⁴ (so named because macrophages “bite” the Heinz bodies out of the red blood cells).

Patients with G6PD deficiency have all the clinical features of hemolytic anemia. On laboratory testing, the Coombs test is negative, the G6PD level is low, and the peripheral smear shows bite cells. The G6PD level is falsely normal or elevated during acute hemolysis because red blood cells deficient in G6PD are removed from circulation and replaced by young red blood cells. The G6PD level is also elevated after blood transfusion. Thus, the G6PD level should be tested 3 months after an acute event.

Hemolysis in G6PD is usually intermittent and self-limited. No treatment is needed except for avoidance of triggers and transfusion for symptomatic anemia. Of note, triggers include some of the drugs commonly used for urinary tract infections (sulfa drugs, nitrofurantoin, phenazopyridine) and antimalarials. Fava beans are also known to cause hemolytic crisis. A complete list of things to avoid can be found at www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISS-it.

There is no commercially available genetic testing kit for G6PD deficiency. Mutation analysis and G6PD gene sequencing are possible but are neither routinely done nor widely available.

BACK TO OUR PATIENT

Our patient’s hemolytic anemia was most likely drug-induced, secondary to a relative deficiency of G6PD. She had been taking nitrofurantoin and phenazopyridine; both of these are oxidizing agents and are known to cause acute hemolytic anemia in people with G6PD deficiency. The G6PD level can be normal after a recent blood transfusion and, as in our patient, during an acute episode of hemolysis.

Because of the strong suspicion of G6PD deficiency, both drugs were stopped when the patient was discharged from the hospital. She did not take either drug for 3 months. Her G6PD level was then retested and was found to be low, confirming the diagnosis. The patient was then advised not to take those drugs again. Since then, her hemoglobin level has remained stable and she has not needed any more blood transfusions.

A 71-year-old woman came to the hospital because of generalized weakness, fatigue, and exertional dyspnea.

She had a history of anemia, recurrent urinary tract infections, and hyperactive bladder. She had been taking nitrofurantoin for a urinary tract infection and phenazopyridine for dysuria, and she noticed that her urine was dark-colored.

She was of northern European descent. She was unaware of any family history of blood-related disorders. She had been admitted to the hospital 6 weeks earlier for symptomatic anemia after taking nitrofurantoin for a urinary tract infection. At that time, she received 2 units of packed red blood cells and then was discharged. Follow-up blood work done 2 weeks later—including a glucose-6 phosphate dehydrogenase (G6PD) assay—was normal.

On physical examination, she was pale and weak. Her hemoglobin level was 5.5 g/dL (reference range 14.0–17.5), with normal white blood cell and platelet counts and an elevated reticulocyte count. A comprehensive metabolic panel showed elevated indirect bilirubin and lactate dehydrogenase levels. A direct Coombs test for autoimmune hemolytic anemia was negative, as was a haptoglobin assay to look for intravascular hemolytic anemia. G6PD levels were normal, yet a peripheral blood smear (Figure 1) showed features of G6PD deficiency.

What was the cause of her anemia?

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

G6PD deficiency is an X-linked disorder¹ that can present as hemolytic anemia. Symptoms of hemolysis can range from mild to severe on exposure to an inciting agent. Men are more commonly affected than women, and affected women are mostly heterozygous. The severity of hemolysis in heterozygous women depends on inactivation of the unaffected X chromosome in some cells.

When exposed to oxidizing agents, people with G6PD deficiency do not have enough nicotinamide adenine dinucleotide phosphate to protect red blood cells.² This leads to oxidative denaturation of hemoglobin, formation of methemoglobin, and denaturation of globulin. These products are insoluble; they collect in red blood cells and are called Heinz bodies.³ When red blood cells containing Heinz bodies pass through the liver and spleen, the insoluble masses are taken up by macrophages, causing hemolysis and the formation of “bite cells”⁴ (so named because macrophages “bite” the Heinz bodies out of the red blood cells).

Patients with G6PD deficiency have all the clinical features of hemolytic anemia. On laboratory testing, the Coombs test is negative, the G6PD level is low, and the peripheral smear shows bite cells. The G6PD level is falsely normal or elevated during acute hemolysis because red blood cells deficient in G6PD are removed from circulation and replaced by young red blood cells. The G6PD level is also elevated after blood transfusion. Thus, the G6PD level should be tested 3 months after an acute event.

Hemolysis in G6PD is usually intermittent and self-limited. No treatment is needed except for avoidance of triggers and transfusion for symptomatic anemia. Of note, triggers include some of the drugs commonly used for urinary tract infections (sulfa drugs, nitrofurantoin, phenazopyridine) and antimalarials. Fava beans are also known to cause hemolytic crisis. A complete list of things to avoid can be found at www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISS-it.

There is no commercially available genetic testing kit for G6PD deficiency. Mutation analysis and G6PD gene sequencing are possible but are neither routinely done nor widely available.

BACK TO OUR PATIENT

Our patient’s hemolytic anemia was most likely drug-induced, secondary to a relative deficiency of G6PD. She had been taking nitrofurantoin and phenazopyridine; both of these are oxidizing agents and are known to cause acute hemolytic anemia in people with G6PD deficiency. The G6PD level can be normal after a recent blood transfusion and, as in our patient, during an acute episode of hemolysis.

Because of the strong suspicion of G6PD deficiency, both drugs were stopped when the patient was discharged from the hospital. She did not take either drug for 3 months. Her G6PD level was then retested and was found to be low, confirming the diagnosis. The patient was then advised not to take those drugs again. Since then, her hemoglobin level has remained stable and she has not needed any more blood transfusions.

Glycosuria used to be a sign of uncontrolled diabetes and was something to be corrected, not a therapeutic mechanism. But now we have a new class of drugs that lower plasma glucose levels by increasing the renal excretion of glucose.

Here, we will review canagliflozin, the first in a new class of drugs for type 2 diabetes: how it works, who is a candidate for it, and what to watch out for.

THE NEED FOR NEW DIABETES DRUGS

Diabetes mellitus affects more than 25.8 million people in the United States—8.3% of the population—and this staggering number is rising.¹ Among US residents age 65 and older, more than 10.9 million (26.9%) have diabetes.¹ People with uncontrolled diabetes are at risk of microvascular complications such as retinopathy, nephropathy, and neuropathy, as well as cardiovascular disease. Diabetes is the leading cause of blindness, chronic kidney disease, and nontraumatic lower-limb amputation in the United States.¹

Type 2 diabetes accounts for more than 90% of cases of diabetes in the United States, Europe, and Canada.² It is characterized by insulin resistance, decreased beta-cell function, and progressive beta-cell decline.³

Current American Diabetes Association guidelines for the treatment of diabetes recommend a hemoglobin A_1c target of less than 7.0%.⁴ Initial management includes lifestyle modifications such as changes in diet and an increase in exercise, as well as consideration of metformin treatment at the same time. If glucose levels remain uncontrolled despite these efforts, other drugs should be added.

A number of oral and injectable antihyperglycemic drugs are available to help achieve this goal, though none is without risk of adverse effects. Those available up to now include metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, gliptins, glucagon-like peptide-1 agonists, amylin analogues, colesevelam, dopamine agonists, and insulin.⁵ Most of the available antihyperglycemics target the liver, pancreas, gut, and muscle to improve insulin sensitivity, reduce insulin resistance, or stimulate insulin secretion.

Despite the abundance of agents, type 2 diabetes remains uncontrolled in many patients. Only 57.1% of participants with previously diagnosed diabetes in the 2003–2006 National Health and Nutrition Examination Survey were at the hemoglobin A_1c goal of less than 7.0%.⁶ Possible reasons for failure include adverse effects such as hypoglycemia, weight gain, and gastrointestinal symptoms resulting in discontinued use, nonadherence to the prescribed regimen, and failure to increase the dosage or to add additional agents, including insulin, to optimize glycemic control as beta-cell function declines over time.

HOW THE KIDNEYS HANDLE GLUCOSE

In the kidney, glucose is filtered in the glomerulus and then is reabsorbed in the proximal tubule. Normally, the filtered glucose is all reabsorbed unless the glucose load exceeds the kidney’s absorptive capacity. Membrane proteins called sodium-glucose cotransporters reabsorb glucose at the proximal tubule and return it into the peripheral circulation. Glucose enters the tubular epithelial cell with sodium by passive cotransport via the sodiumglucose cotransporters, and then exits on the other side via the glucose transporter GLUT in the basolateral membrane.

Two sodium-glucose transporters that act in the proximal tubule of the kidney have been identified: SGLT1 and SGLT2. SGLT2 reabsorbs most of the glucose in the early segment of the proximal tubule, while SLGT1 reabsorbs the remaining glucose at the distal end.⁷ SGLT2 is responsible for more than 90% of renal tubular reabsorption of glucose and is found only in the proximal tubule, whereas SGLT1 is found mainly in the gastrointestinal tract.⁸

Patients with type 2 diabetes have a higher capacity for glucose reabsorption in the proximal tubule as a result of the up-regulation of SGLT2.⁹

SGLT2 INHIBITORS AND TYPE 2 DIABETES

Drugs that inhibit SGLT2 block reabsorption of glucose in the proximal tubule, lowering the renal threshold for glucose and thereby increasing urinary glucose excretion and lowering the serum glucose level in patients with hyperglycemia. This mechanism of action is insulin-independent.

On March 29, 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States for the treatment of type 2 diabetes.¹⁰ However, it is not the first of its class to be introduced.

Dapagliflozin was the first SGLT2 inhibitor approved in Europe and has been available there since November 2012. However, the US Food and Drug Administration withheld its approval in the United States in January 2012 because of concerns of a possible association with cancer, specifically breast and bladder cancers, as well as possible liver injury.¹⁰ Canagliflozin does not appear to share this risk.

Several other SGLT2 inhibitors may soon be available. Empagliflozin is in phase III trials, and the manufacturer has filed for approval in the United States. Ipragliflozin is awaiting approval in Japan.

CANAGLIFLOZIN: PHARMACOKINETICS AND THERAPEUTIC EFFICACY

Canagliflozin reaches its peak plasma concentration within 1 to 2 hours of oral administration.¹¹ Its half-life is 10.6 hours with a 100-mg dose and 13.1 hours with a 300-mg dose. A steady state is typically achieved in 4 to 5 days.¹¹

Canagliflozin lowers fasting plasma glucose and hemoglobin A_1c levels in a dose-dependent manner.^10,11 These effects are independent of age, sex, body mass index, and race.¹² Postprandial glucose levels are also lowered.

Other potential benefits of canagliflozin include lowering of the systolic blood pressure and, especially important in obese people with type 2 diabetes, weight loss.¹² Aside from metformin, which occasionally results in modest weight loss, other oral drugs used in treating type 2 diabetes are weight-neutral or can cause weight gain.

Trials of canagliflozin

Nine phase III trials of canagliflozin have enrolled 10,285 patients, in one of the largest clinical trial programs in type 2 diabetes to date.¹⁰ Several of these trials evaluated canagliflozin as monotherapy, whereas others assessed its effect as an add-on therapy in combination with another antihyperglycemic agent such as a sulfonylurea, metformin, pioglitazone, or insulin. There has not yet been a trial directly comparing canagliflozin with metformin.

Four of the placebo-controlled trials evaluated canagliflozin as monotherapy, canagliflozin added to metformin alone, canagliflozin added to metformin plus glimepiride, and canagliflozin added to metformin plus pioglitazone.

When canagliflozin was used as monotherapy, hemoglobin A_1c levels at 26 weeks were an absolute 0.91% lower in the canagliflozin 100 mg/day group than in the placebo group, and an absolute 1.16% lower in the canagliflozin 300 mg/day group than in the placebo group (P < .001 for both).¹² Patients lost 2.8% of their body weight with canagliflozin 100 mg and 3.3% with canagliflozin 300 mg, compared with 0.6% with placebo. Systolic blood pressure fell by a mean of 3.7 mm Hg with the 100-mg dose and by a mean of 5.4 mm Hg with the 300-mg dose compared with placebo (P < .001 for both dose groups).¹²

When canagliflozin was added to metformin, with glimepiride as the comparator drug, there was a 5.2% weight reduction with the 100-mg dose, a 5.7% reduction with 300 mg, and a 1% gain with glimepiride. Hemoglobin A_1c fell about equally in the three groups.¹¹

When canagliflozin was added to metformin and a sulfonylurea, with sitagliptin as the comparator third drug, the 300-mg canagliflozin dosage group had a 2.8% weight reduction.¹¹

WHAT ARE THE ADVERSE EFFECTS?

Overall, canagliflozin seems to be well tolerated. The most common adverse effects reported in the clinical trials were genital yeast infections, urinary tract infections, and increased urination.

Genital yeast infections were more common in women than in men, occurring in 10.4% of women who received canagliflozin 100 mg and in 11.4% of women who received 300 mg, compared with only 3.2% in the placebo group.¹¹

Urinary tract infections occurred in 5.9% of the 100-mg group and in 4.3% of the 300-mg group, compared with 4.0% of the placebo group.¹¹

Postural hypotension. Lowering of blood pressure and symptoms of postural hypotension were also reported, and these may be attributed to the drug’s mild osmotic diuretic effect. The risk of adverse effects of volume depletion was dose-dependent; in patients over age 75, they occurred in 4.9% of those taking 100 mg and in 8.7% of those taking 300 mg, compared with 2.6% of those in the placebo or active-comparator groups.¹¹ Therefore, one should exercise particular caution when starting this drug in the elderly or in patients taking diuretics or multiple antihypertensive drugs.

Hypoglycemia. When canagliflozin was used as monotherapy, the incidence of hypoglycemia over 26 weeks was similar to that with placebo, occurring in 3.6% of the 100-mg group, 3.0% of the 300-mg group, and 2.6% of the placebo group.¹² Canagliflozin was associated with fewer episodes of hypoglycemia than were sulfonylureas, and the number of episodes was similar to that in patients taking gliptins. There was a higher overall incidence of hypoglycemia when canagliflozin was used in combination with a sulfonylurea or with insulin than when it was used as monotherapy.¹¹

Hyperkalemia. Patients with moderate renal impairment or who are on potassiumsparing drugs or drugs that interfere with the renin-angiotensin-aldosterone system may be at higher risk of hyperkalemia, so close monitoring of potassium is recommended. There was also a dose-dependent increase in serum phosphate and magnesium levels, more notably in patients with moderate renal impairment within the first 3 weeks of starting the drug.¹¹

Patients on canagliflozin who are also taking digoxin, ritonavir, phenytoin, phenobarbital, or rifampin should be closely monitored because of the risk of drug-drug interactions.¹¹ Specifically, there was an increase in mean peak digoxin concentrations when used with canagliflozin 300 mg, and the use of phenytoin, phenobarbital, and ritonavir decreased the efficacy of canagliflozin.

WHAT ARE THE CARDIOVASCULAR RISKS OR LONG-TERM CONCERNS?

Dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) may be seen with canagliflozin. Mean changes from baseline compared with placebo were 4.4 mg/dL (4.5%) with canagliflozin 100 mg and 8.3 mg/dL (8%) with canagliflozin 300 mg.¹¹

There was also an increase in non-high-density lipoprotein cholesterol (non-HDL-C).¹² Compared with placebo, mean non-HDL-C levels rose by 2.1 mg/dL (1.5%) with canagliflozin 100 mg and 5.1 mg/dL (3.6%) with 300 mg.¹¹

In the 26-week canagliflozin monotherapy trial, archived blood samples in a small subgroup of patients (n = 349) were measured for apolipoprotein-B, which was found to increase by 1.2% with canagliflozin 100 mg and 3.5% with canagliflozin 300 mg, compared with 0.9% in the placebo group.¹²

Although small, the increase in LDL-C seen with this drug could be a concern, as diabetic patients are already at higher risk of cardiovascular events. The mechanism of this increase is not yet known, though it may be related to metabolic changes from urinary glucose excretion.¹²

The Canagliflozin Cardiovascular Assessment Study (CANVAS) is a randomized placebo-controlled trial in more than 4,000 patients with type 2 diabetes who have a history of or are at high risk of cardiovascular events. Currently under way, it is evaluating the occurrence of major adverse cardiovascular events (the primary end point) in patients randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo once daily for up to 4 years. Secondary end points will be the drug’s effects on fasting plasma insulin and glucose, progression of albuminuria, body weight, blood pressure, HDL-C, LDL-C, bone mineral density, markers of bone turnover, and body composition.¹⁰ This trial will run for 9 years, to be completed in 2018.¹³

The CANVAS investigators have already reported that within the first month of treatment, 13 patients taking canagliflozin suffered a major cardiovascular event, including stroke (one of which was fatal) compared with just one patient taking placebo. These events were not seen after the first month. The hazard ratio for major adverse cardiovascular events within the first 30 days was 6.49, but this dropped to 0.89 after the first 30 days.¹⁰

Additional issues that should be addressed in long-term postmarketing studies include possible relationships with cancers and pancreatitis and the safety of the drug in pregnancy and in children with diabetes.¹⁰

WHO IS A CANDIDATE FOR THIS DRUG?

Canagliflozin is approved for use as monotherapy in addition to lifestyle modifications. It is also approved for use with other antihyperglycemic drugs, including metformin.

Obese patients with type 2 diabetes and normal kidney function may have the greatest benefit. Because of canagliflozin’s insulinin-dependent mechanism of action, patients with both early and late type 2 diabetes may benefit from its ability to lower hemoglobin A_1c and blood glucose.¹⁴

Although it can be used in patients with moderate (but not severe) kidney disease, canagliflozin does not appear to be as effective in these patients, who had higher rates of adverse effects.¹¹ It is not indicated for patients with type 1 diabetes, type 2 diabetes with ketonuria, or end-stage renal disease (estimated glomerular filtration rate < 45 mL/min or receiving dialysis).¹¹ It also is not yet recommended for use in pregnant women or patients under age 18.

The recommended starting dose of canagliflozin is 100 mg once daily, taken with breakfast. This can be increased to 300 mg once daily if tolerated. However, patients with an estimated glomerular filtration rate of 45 to 60 mL/min should not exceed the 100- mg dose. No dose adjustment is required in patients with mild to moderate hepatic impairment. It is not recommended, however, in patients with severe hepatic impairment.¹¹

Comment. Although canagliflozin is approved as monotherapy, metformin remains my choice for first-line oral therapy. Because canagliflozin is more expensive and its long-term affects are still relatively unknown, I prefer to use it as an adjunct, and believe it will be a useful addition, especially in obese patients who are seeking to lose weight.

WHAT IS THE COST OF THIS DRUG?

The suggested price is $10.53 per tablet (AmerisourceBergen), which is comparable to that of other newer drugs for type 2 diabetes.

THE BOTTOM LINE

The availability of canagliflozin as an additional oral antihyperglycemic option may prove helpful in managing patients with type 2 diabetes who experience adverse effects with other antihyperglycemic drugs.

As with any new drug, questions remain about the long-term risks of canagliflozin. However, it seems to be well tolerated, especially in patients with normal kidney function, and poses a low risk of hypoglycemia. The slight increase in LDL-C may prompt more aggressive lipid management. Whether blood pressure-lowering and weight loss will offset this increase in LDL-C is yet to be determined. Ongoing studies will help to further elucidate whether there is an increased risk of cardiovascular events.

Finally, canagliflozin distinguishes itself from other oral diabetes drugs by its added benefit of weight loss, an appealing side effect, especially in the growing population of obese individuals with type 2 diabetes mellitus.

Glycosuria used to be a sign of uncontrolled diabetes and was something to be corrected, not a therapeutic mechanism. But now we have a new class of drugs that lower plasma glucose levels by increasing the renal excretion of glucose.

Here, we will review canagliflozin, the first in a new class of drugs for type 2 diabetes: how it works, who is a candidate for it, and what to watch out for.

THE NEED FOR NEW DIABETES DRUGS

Diabetes mellitus affects more than 25.8 million people in the United States—8.3% of the population—and this staggering number is rising.¹ Among US residents age 65 and older, more than 10.9 million (26.9%) have diabetes.¹ People with uncontrolled diabetes are at risk of microvascular complications such as retinopathy, nephropathy, and neuropathy, as well as cardiovascular disease. Diabetes is the leading cause of blindness, chronic kidney disease, and nontraumatic lower-limb amputation in the United States.¹

Type 2 diabetes accounts for more than 90% of cases of diabetes in the United States, Europe, and Canada.² It is characterized by insulin resistance, decreased beta-cell function, and progressive beta-cell decline.³

Current American Diabetes Association guidelines for the treatment of diabetes recommend a hemoglobin A_1c target of less than 7.0%.⁴ Initial management includes lifestyle modifications such as changes in diet and an increase in exercise, as well as consideration of metformin treatment at the same time. If glucose levels remain uncontrolled despite these efforts, other drugs should be added.

A number of oral and injectable antihyperglycemic drugs are available to help achieve this goal, though none is without risk of adverse effects. Those available up to now include metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, gliptins, glucagon-like peptide-1 agonists, amylin analogues, colesevelam, dopamine agonists, and insulin.⁵ Most of the available antihyperglycemics target the liver, pancreas, gut, and muscle to improve insulin sensitivity, reduce insulin resistance, or stimulate insulin secretion.

Despite the abundance of agents, type 2 diabetes remains uncontrolled in many patients. Only 57.1% of participants with previously diagnosed diabetes in the 2003–2006 National Health and Nutrition Examination Survey were at the hemoglobin A_1c goal of less than 7.0%.⁶ Possible reasons for failure include adverse effects such as hypoglycemia, weight gain, and gastrointestinal symptoms resulting in discontinued use, nonadherence to the prescribed regimen, and failure to increase the dosage or to add additional agents, including insulin, to optimize glycemic control as beta-cell function declines over time.

HOW THE KIDNEYS HANDLE GLUCOSE

In the kidney, glucose is filtered in the glomerulus and then is reabsorbed in the proximal tubule. Normally, the filtered glucose is all reabsorbed unless the glucose load exceeds the kidney’s absorptive capacity. Membrane proteins called sodium-glucose cotransporters reabsorb glucose at the proximal tubule and return it into the peripheral circulation. Glucose enters the tubular epithelial cell with sodium by passive cotransport via the sodiumglucose cotransporters, and then exits on the other side via the glucose transporter GLUT in the basolateral membrane.

Two sodium-glucose transporters that act in the proximal tubule of the kidney have been identified: SGLT1 and SGLT2. SGLT2 reabsorbs most of the glucose in the early segment of the proximal tubule, while SLGT1 reabsorbs the remaining glucose at the distal end.⁷ SGLT2 is responsible for more than 90% of renal tubular reabsorption of glucose and is found only in the proximal tubule, whereas SGLT1 is found mainly in the gastrointestinal tract.⁸

Patients with type 2 diabetes have a higher capacity for glucose reabsorption in the proximal tubule as a result of the up-regulation of SGLT2.⁹

SGLT2 INHIBITORS AND TYPE 2 DIABETES

Drugs that inhibit SGLT2 block reabsorption of glucose in the proximal tubule, lowering the renal threshold for glucose and thereby increasing urinary glucose excretion and lowering the serum glucose level in patients with hyperglycemia. This mechanism of action is insulin-independent.

On March 29, 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States for the treatment of type 2 diabetes.¹⁰ However, it is not the first of its class to be introduced.

Dapagliflozin was the first SGLT2 inhibitor approved in Europe and has been available there since November 2012. However, the US Food and Drug Administration withheld its approval in the United States in January 2012 because of concerns of a possible association with cancer, specifically breast and bladder cancers, as well as possible liver injury.¹⁰ Canagliflozin does not appear to share this risk.

Several other SGLT2 inhibitors may soon be available. Empagliflozin is in phase III trials, and the manufacturer has filed for approval in the United States. Ipragliflozin is awaiting approval in Japan.

CANAGLIFLOZIN: PHARMACOKINETICS AND THERAPEUTIC EFFICACY

Canagliflozin reaches its peak plasma concentration within 1 to 2 hours of oral administration.¹¹ Its half-life is 10.6 hours with a 100-mg dose and 13.1 hours with a 300-mg dose. A steady state is typically achieved in 4 to 5 days.¹¹

Canagliflozin lowers fasting plasma glucose and hemoglobin A_1c levels in a dose-dependent manner.^10,11 These effects are independent of age, sex, body mass index, and race.¹² Postprandial glucose levels are also lowered.

Other potential benefits of canagliflozin include lowering of the systolic blood pressure and, especially important in obese people with type 2 diabetes, weight loss.¹² Aside from metformin, which occasionally results in modest weight loss, other oral drugs used in treating type 2 diabetes are weight-neutral or can cause weight gain.

Trials of canagliflozin

Nine phase III trials of canagliflozin have enrolled 10,285 patients, in one of the largest clinical trial programs in type 2 diabetes to date.¹⁰ Several of these trials evaluated canagliflozin as monotherapy, whereas others assessed its effect as an add-on therapy in combination with another antihyperglycemic agent such as a sulfonylurea, metformin, pioglitazone, or insulin. There has not yet been a trial directly comparing canagliflozin with metformin.

Four of the placebo-controlled trials evaluated canagliflozin as monotherapy, canagliflozin added to metformin alone, canagliflozin added to metformin plus glimepiride, and canagliflozin added to metformin plus pioglitazone.

When canagliflozin was used as monotherapy, hemoglobin A_1c levels at 26 weeks were an absolute 0.91% lower in the canagliflozin 100 mg/day group than in the placebo group, and an absolute 1.16% lower in the canagliflozin 300 mg/day group than in the placebo group (P < .001 for both).¹² Patients lost 2.8% of their body weight with canagliflozin 100 mg and 3.3% with canagliflozin 300 mg, compared with 0.6% with placebo. Systolic blood pressure fell by a mean of 3.7 mm Hg with the 100-mg dose and by a mean of 5.4 mm Hg with the 300-mg dose compared with placebo (P < .001 for both dose groups).¹²

When canagliflozin was added to metformin, with glimepiride as the comparator drug, there was a 5.2% weight reduction with the 100-mg dose, a 5.7% reduction with 300 mg, and a 1% gain with glimepiride. Hemoglobin A_1c fell about equally in the three groups.¹¹

When canagliflozin was added to metformin and a sulfonylurea, with sitagliptin as the comparator third drug, the 300-mg canagliflozin dosage group had a 2.8% weight reduction.¹¹

WHAT ARE THE ADVERSE EFFECTS?

Overall, canagliflozin seems to be well tolerated. The most common adverse effects reported in the clinical trials were genital yeast infections, urinary tract infections, and increased urination.

Genital yeast infections were more common in women than in men, occurring in 10.4% of women who received canagliflozin 100 mg and in 11.4% of women who received 300 mg, compared with only 3.2% in the placebo group.¹¹

Urinary tract infections occurred in 5.9% of the 100-mg group and in 4.3% of the 300-mg group, compared with 4.0% of the placebo group.¹¹

Postural hypotension. Lowering of blood pressure and symptoms of postural hypotension were also reported, and these may be attributed to the drug’s mild osmotic diuretic effect. The risk of adverse effects of volume depletion was dose-dependent; in patients over age 75, they occurred in 4.9% of those taking 100 mg and in 8.7% of those taking 300 mg, compared with 2.6% of those in the placebo or active-comparator groups.¹¹ Therefore, one should exercise particular caution when starting this drug in the elderly or in patients taking diuretics or multiple antihypertensive drugs.

Hypoglycemia. When canagliflozin was used as monotherapy, the incidence of hypoglycemia over 26 weeks was similar to that with placebo, occurring in 3.6% of the 100-mg group, 3.0% of the 300-mg group, and 2.6% of the placebo group.¹² Canagliflozin was associated with fewer episodes of hypoglycemia than were sulfonylureas, and the number of episodes was similar to that in patients taking gliptins. There was a higher overall incidence of hypoglycemia when canagliflozin was used in combination with a sulfonylurea or with insulin than when it was used as monotherapy.¹¹

Hyperkalemia. Patients with moderate renal impairment or who are on potassiumsparing drugs or drugs that interfere with the renin-angiotensin-aldosterone system may be at higher risk of hyperkalemia, so close monitoring of potassium is recommended. There was also a dose-dependent increase in serum phosphate and magnesium levels, more notably in patients with moderate renal impairment within the first 3 weeks of starting the drug.¹¹

Patients on canagliflozin who are also taking digoxin, ritonavir, phenytoin, phenobarbital, or rifampin should be closely monitored because of the risk of drug-drug interactions.¹¹ Specifically, there was an increase in mean peak digoxin concentrations when used with canagliflozin 300 mg, and the use of phenytoin, phenobarbital, and ritonavir decreased the efficacy of canagliflozin.

WHAT ARE THE CARDIOVASCULAR RISKS OR LONG-TERM CONCERNS?

Dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) may be seen with canagliflozin. Mean changes from baseline compared with placebo were 4.4 mg/dL (4.5%) with canagliflozin 100 mg and 8.3 mg/dL (8%) with canagliflozin 300 mg.¹¹

There was also an increase in non-high-density lipoprotein cholesterol (non-HDL-C).¹² Compared with placebo, mean non-HDL-C levels rose by 2.1 mg/dL (1.5%) with canagliflozin 100 mg and 5.1 mg/dL (3.6%) with 300 mg.¹¹

In the 26-week canagliflozin monotherapy trial, archived blood samples in a small subgroup of patients (n = 349) were measured for apolipoprotein-B, which was found to increase by 1.2% with canagliflozin 100 mg and 3.5% with canagliflozin 300 mg, compared with 0.9% in the placebo group.¹²

Although small, the increase in LDL-C seen with this drug could be a concern, as diabetic patients are already at higher risk of cardiovascular events. The mechanism of this increase is not yet known, though it may be related to metabolic changes from urinary glucose excretion.¹²

The Canagliflozin Cardiovascular Assessment Study (CANVAS) is a randomized placebo-controlled trial in more than 4,000 patients with type 2 diabetes who have a history of or are at high risk of cardiovascular events. Currently under way, it is evaluating the occurrence of major adverse cardiovascular events (the primary end point) in patients randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo once daily for up to 4 years. Secondary end points will be the drug’s effects on fasting plasma insulin and glucose, progression of albuminuria, body weight, blood pressure, HDL-C, LDL-C, bone mineral density, markers of bone turnover, and body composition.¹⁰ This trial will run for 9 years, to be completed in 2018.¹³

The CANVAS investigators have already reported that within the first month of treatment, 13 patients taking canagliflozin suffered a major cardiovascular event, including stroke (one of which was fatal) compared with just one patient taking placebo. These events were not seen after the first month. The hazard ratio for major adverse cardiovascular events within the first 30 days was 6.49, but this dropped to 0.89 after the first 30 days.¹⁰

Additional issues that should be addressed in long-term postmarketing studies include possible relationships with cancers and pancreatitis and the safety of the drug in pregnancy and in children with diabetes.¹⁰

WHO IS A CANDIDATE FOR THIS DRUG?

Canagliflozin is approved for use as monotherapy in addition to lifestyle modifications. It is also approved for use with other antihyperglycemic drugs, including metformin.

Obese patients with type 2 diabetes and normal kidney function may have the greatest benefit. Because of canagliflozin’s insulinin-dependent mechanism of action, patients with both early and late type 2 diabetes may benefit from its ability to lower hemoglobin A_1c and blood glucose.¹⁴

Although it can be used in patients with moderate (but not severe) kidney disease, canagliflozin does not appear to be as effective in these patients, who had higher rates of adverse effects.¹¹ It is not indicated for patients with type 1 diabetes, type 2 diabetes with ketonuria, or end-stage renal disease (estimated glomerular filtration rate < 45 mL/min or receiving dialysis).¹¹ It also is not yet recommended for use in pregnant women or patients under age 18.

The recommended starting dose of canagliflozin is 100 mg once daily, taken with breakfast. This can be increased to 300 mg once daily if tolerated. However, patients with an estimated glomerular filtration rate of 45 to 60 mL/min should not exceed the 100- mg dose. No dose adjustment is required in patients with mild to moderate hepatic impairment. It is not recommended, however, in patients with severe hepatic impairment.¹¹

Comment. Although canagliflozin is approved as monotherapy, metformin remains my choice for first-line oral therapy. Because canagliflozin is more expensive and its long-term affects are still relatively unknown, I prefer to use it as an adjunct, and believe it will be a useful addition, especially in obese patients who are seeking to lose weight.

WHAT IS THE COST OF THIS DRUG?

The suggested price is $10.53 per tablet (AmerisourceBergen), which is comparable to that of other newer drugs for type 2 diabetes.

THE BOTTOM LINE

The availability of canagliflozin as an additional oral antihyperglycemic option may prove helpful in managing patients with type 2 diabetes who experience adverse effects with other antihyperglycemic drugs.

As with any new drug, questions remain about the long-term risks of canagliflozin. However, it seems to be well tolerated, especially in patients with normal kidney function, and poses a low risk of hypoglycemia. The slight increase in LDL-C may prompt more aggressive lipid management. Whether blood pressure-lowering and weight loss will offset this increase in LDL-C is yet to be determined. Ongoing studies will help to further elucidate whether there is an increased risk of cardiovascular events.

Finally, canagliflozin distinguishes itself from other oral diabetes drugs by its added benefit of weight loss, an appealing side effect, especially in the growing population of obese individuals with type 2 diabetes mellitus.

Glycosuria used to be a sign of uncontrolled diabetes and was something to be corrected, not a therapeutic mechanism. But now we have a new class of drugs that lower plasma glucose levels by increasing the renal excretion of glucose.

Here, we will review canagliflozin, the first in a new class of drugs for type 2 diabetes: how it works, who is a candidate for it, and what to watch out for.

THE NEED FOR NEW DIABETES DRUGS

Diabetes mellitus affects more than 25.8 million people in the United States—8.3% of the population—and this staggering number is rising.¹ Among US residents age 65 and older, more than 10.9 million (26.9%) have diabetes.¹ People with uncontrolled diabetes are at risk of microvascular complications such as retinopathy, nephropathy, and neuropathy, as well as cardiovascular disease. Diabetes is the leading cause of blindness, chronic kidney disease, and nontraumatic lower-limb amputation in the United States.¹

Type 2 diabetes accounts for more than 90% of cases of diabetes in the United States, Europe, and Canada.² It is characterized by insulin resistance, decreased beta-cell function, and progressive beta-cell decline.³

Current American Diabetes Association guidelines for the treatment of diabetes recommend a hemoglobin A_1c target of less than 7.0%.⁴ Initial management includes lifestyle modifications such as changes in diet and an increase in exercise, as well as consideration of metformin treatment at the same time. If glucose levels remain uncontrolled despite these efforts, other drugs should be added.

A number of oral and injectable antihyperglycemic drugs are available to help achieve this goal, though none is without risk of adverse effects. Those available up to now include metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, gliptins, glucagon-like peptide-1 agonists, amylin analogues, colesevelam, dopamine agonists, and insulin.⁵ Most of the available antihyperglycemics target the liver, pancreas, gut, and muscle to improve insulin sensitivity, reduce insulin resistance, or stimulate insulin secretion.

Despite the abundance of agents, type 2 diabetes remains uncontrolled in many patients. Only 57.1% of participants with previously diagnosed diabetes in the 2003–2006 National Health and Nutrition Examination Survey were at the hemoglobin A_1c goal of less than 7.0%.⁶ Possible reasons for failure include adverse effects such as hypoglycemia, weight gain, and gastrointestinal symptoms resulting in discontinued use, nonadherence to the prescribed regimen, and failure to increase the dosage or to add additional agents, including insulin, to optimize glycemic control as beta-cell function declines over time.

HOW THE KIDNEYS HANDLE GLUCOSE

In the kidney, glucose is filtered in the glomerulus and then is reabsorbed in the proximal tubule. Normally, the filtered glucose is all reabsorbed unless the glucose load exceeds the kidney’s absorptive capacity. Membrane proteins called sodium-glucose cotransporters reabsorb glucose at the proximal tubule and return it into the peripheral circulation. Glucose enters the tubular epithelial cell with sodium by passive cotransport via the sodiumglucose cotransporters, and then exits on the other side via the glucose transporter GLUT in the basolateral membrane.

Two sodium-glucose transporters that act in the proximal tubule of the kidney have been identified: SGLT1 and SGLT2. SGLT2 reabsorbs most of the glucose in the early segment of the proximal tubule, while SLGT1 reabsorbs the remaining glucose at the distal end.⁷ SGLT2 is responsible for more than 90% of renal tubular reabsorption of glucose and is found only in the proximal tubule, whereas SGLT1 is found mainly in the gastrointestinal tract.⁸

Patients with type 2 diabetes have a higher capacity for glucose reabsorption in the proximal tubule as a result of the up-regulation of SGLT2.⁹

SGLT2 INHIBITORS AND TYPE 2 DIABETES

Drugs that inhibit SGLT2 block reabsorption of glucose in the proximal tubule, lowering the renal threshold for glucose and thereby increasing urinary glucose excretion and lowering the serum glucose level in patients with hyperglycemia. This mechanism of action is insulin-independent.

On March 29, 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States for the treatment of type 2 diabetes.¹⁰ However, it is not the first of its class to be introduced.

Dapagliflozin was the first SGLT2 inhibitor approved in Europe and has been available there since November 2012. However, the US Food and Drug Administration withheld its approval in the United States in January 2012 because of concerns of a possible association with cancer, specifically breast and bladder cancers, as well as possible liver injury.¹⁰ Canagliflozin does not appear to share this risk.

Several other SGLT2 inhibitors may soon be available. Empagliflozin is in phase III trials, and the manufacturer has filed for approval in the United States. Ipragliflozin is awaiting approval in Japan.

CANAGLIFLOZIN: PHARMACOKINETICS AND THERAPEUTIC EFFICACY

Canagliflozin reaches its peak plasma concentration within 1 to 2 hours of oral administration.¹¹ Its half-life is 10.6 hours with a 100-mg dose and 13.1 hours with a 300-mg dose. A steady state is typically achieved in 4 to 5 days.¹¹

Canagliflozin lowers fasting plasma glucose and hemoglobin A_1c levels in a dose-dependent manner.^10,11 These effects are independent of age, sex, body mass index, and race.¹² Postprandial glucose levels are also lowered.

Other potential benefits of canagliflozin include lowering of the systolic blood pressure and, especially important in obese people with type 2 diabetes, weight loss.¹² Aside from metformin, which occasionally results in modest weight loss, other oral drugs used in treating type 2 diabetes are weight-neutral or can cause weight gain.

Trials of canagliflozin

Nine phase III trials of canagliflozin have enrolled 10,285 patients, in one of the largest clinical trial programs in type 2 diabetes to date.¹⁰ Several of these trials evaluated canagliflozin as monotherapy, whereas others assessed its effect as an add-on therapy in combination with another antihyperglycemic agent such as a sulfonylurea, metformin, pioglitazone, or insulin. There has not yet been a trial directly comparing canagliflozin with metformin.

Four of the placebo-controlled trials evaluated canagliflozin as monotherapy, canagliflozin added to metformin alone, canagliflozin added to metformin plus glimepiride, and canagliflozin added to metformin plus pioglitazone.

When canagliflozin was used as monotherapy, hemoglobin A_1c levels at 26 weeks were an absolute 0.91% lower in the canagliflozin 100 mg/day group than in the placebo group, and an absolute 1.16% lower in the canagliflozin 300 mg/day group than in the placebo group (P < .001 for both).¹² Patients lost 2.8% of their body weight with canagliflozin 100 mg and 3.3% with canagliflozin 300 mg, compared with 0.6% with placebo. Systolic blood pressure fell by a mean of 3.7 mm Hg with the 100-mg dose and by a mean of 5.4 mm Hg with the 300-mg dose compared with placebo (P < .001 for both dose groups).¹²

When canagliflozin was added to metformin, with glimepiride as the comparator drug, there was a 5.2% weight reduction with the 100-mg dose, a 5.7% reduction with 300 mg, and a 1% gain with glimepiride. Hemoglobin A_1c fell about equally in the three groups.¹¹

When canagliflozin was added to metformin and a sulfonylurea, with sitagliptin as the comparator third drug, the 300-mg canagliflozin dosage group had a 2.8% weight reduction.¹¹

WHAT ARE THE ADVERSE EFFECTS?

Overall, canagliflozin seems to be well tolerated. The most common adverse effects reported in the clinical trials were genital yeast infections, urinary tract infections, and increased urination.

Genital yeast infections were more common in women than in men, occurring in 10.4% of women who received canagliflozin 100 mg and in 11.4% of women who received 300 mg, compared with only 3.2% in the placebo group.¹¹

Urinary tract infections occurred in 5.9% of the 100-mg group and in 4.3% of the 300-mg group, compared with 4.0% of the placebo group.¹¹

Postural hypotension. Lowering of blood pressure and symptoms of postural hypotension were also reported, and these may be attributed to the drug’s mild osmotic diuretic effect. The risk of adverse effects of volume depletion was dose-dependent; in patients over age 75, they occurred in 4.9% of those taking 100 mg and in 8.7% of those taking 300 mg, compared with 2.6% of those in the placebo or active-comparator groups.¹¹ Therefore, one should exercise particular caution when starting this drug in the elderly or in patients taking diuretics or multiple antihypertensive drugs.

Hypoglycemia. When canagliflozin was used as monotherapy, the incidence of hypoglycemia over 26 weeks was similar to that with placebo, occurring in 3.6% of the 100-mg group, 3.0% of the 300-mg group, and 2.6% of the placebo group.¹² Canagliflozin was associated with fewer episodes of hypoglycemia than were sulfonylureas, and the number of episodes was similar to that in patients taking gliptins. There was a higher overall incidence of hypoglycemia when canagliflozin was used in combination with a sulfonylurea or with insulin than when it was used as monotherapy.¹¹

Hyperkalemia. Patients with moderate renal impairment or who are on potassiumsparing drugs or drugs that interfere with the renin-angiotensin-aldosterone system may be at higher risk of hyperkalemia, so close monitoring of potassium is recommended. There was also a dose-dependent increase in serum phosphate and magnesium levels, more notably in patients with moderate renal impairment within the first 3 weeks of starting the drug.¹¹

Patients on canagliflozin who are also taking digoxin, ritonavir, phenytoin, phenobarbital, or rifampin should be closely monitored because of the risk of drug-drug interactions.¹¹ Specifically, there was an increase in mean peak digoxin concentrations when used with canagliflozin 300 mg, and the use of phenytoin, phenobarbital, and ritonavir decreased the efficacy of canagliflozin.

WHAT ARE THE CARDIOVASCULAR RISKS OR LONG-TERM CONCERNS?

Dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) may be seen with canagliflozin. Mean changes from baseline compared with placebo were 4.4 mg/dL (4.5%) with canagliflozin 100 mg and 8.3 mg/dL (8%) with canagliflozin 300 mg.¹¹

There was also an increase in non-high-density lipoprotein cholesterol (non-HDL-C).¹² Compared with placebo, mean non-HDL-C levels rose by 2.1 mg/dL (1.5%) with canagliflozin 100 mg and 5.1 mg/dL (3.6%) with 300 mg.¹¹

In the 26-week canagliflozin monotherapy trial, archived blood samples in a small subgroup of patients (n = 349) were measured for apolipoprotein-B, which was found to increase by 1.2% with canagliflozin 100 mg and 3.5% with canagliflozin 300 mg, compared with 0.9% in the placebo group.¹²

Although small, the increase in LDL-C seen with this drug could be a concern, as diabetic patients are already at higher risk of cardiovascular events. The mechanism of this increase is not yet known, though it may be related to metabolic changes from urinary glucose excretion.¹²

The Canagliflozin Cardiovascular Assessment Study (CANVAS) is a randomized placebo-controlled trial in more than 4,000 patients with type 2 diabetes who have a history of or are at high risk of cardiovascular events. Currently under way, it is evaluating the occurrence of major adverse cardiovascular events (the primary end point) in patients randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo once daily for up to 4 years. Secondary end points will be the drug’s effects on fasting plasma insulin and glucose, progression of albuminuria, body weight, blood pressure, HDL-C, LDL-C, bone mineral density, markers of bone turnover, and body composition.¹⁰ This trial will run for 9 years, to be completed in 2018.¹³

The CANVAS investigators have already reported that within the first month of treatment, 13 patients taking canagliflozin suffered a major cardiovascular event, including stroke (one of which was fatal) compared with just one patient taking placebo. These events were not seen after the first month. The hazard ratio for major adverse cardiovascular events within the first 30 days was 6.49, but this dropped to 0.89 after the first 30 days.¹⁰

Additional issues that should be addressed in long-term postmarketing studies include possible relationships with cancers and pancreatitis and the safety of the drug in pregnancy and in children with diabetes.¹⁰

WHO IS A CANDIDATE FOR THIS DRUG?

Canagliflozin is approved for use as monotherapy in addition to lifestyle modifications. It is also approved for use with other antihyperglycemic drugs, including metformin.

Obese patients with type 2 diabetes and normal kidney function may have the greatest benefit. Because of canagliflozin’s insulinin-dependent mechanism of action, patients with both early and late type 2 diabetes may benefit from its ability to lower hemoglobin A_1c and blood glucose.¹⁴

Although it can be used in patients with moderate (but not severe) kidney disease, canagliflozin does not appear to be as effective in these patients, who had higher rates of adverse effects.¹¹ It is not indicated for patients with type 1 diabetes, type 2 diabetes with ketonuria, or end-stage renal disease (estimated glomerular filtration rate < 45 mL/min or receiving dialysis).¹¹ It also is not yet recommended for use in pregnant women or patients under age 18.

The recommended starting dose of canagliflozin is 100 mg once daily, taken with breakfast. This can be increased to 300 mg once daily if tolerated. However, patients with an estimated glomerular filtration rate of 45 to 60 mL/min should not exceed the 100- mg dose. No dose adjustment is required in patients with mild to moderate hepatic impairment. It is not recommended, however, in patients with severe hepatic impairment.¹¹

Comment. Although canagliflozin is approved as monotherapy, metformin remains my choice for first-line oral therapy. Because canagliflozin is more expensive and its long-term affects are still relatively unknown, I prefer to use it as an adjunct, and believe it will be a useful addition, especially in obese patients who are seeking to lose weight.

WHAT IS THE COST OF THIS DRUG?

The suggested price is $10.53 per tablet (AmerisourceBergen), which is comparable to that of other newer drugs for type 2 diabetes.

THE BOTTOM LINE

The availability of canagliflozin as an additional oral antihyperglycemic option may prove helpful in managing patients with type 2 diabetes who experience adverse effects with other antihyperglycemic drugs.

As with any new drug, questions remain about the long-term risks of canagliflozin. However, it seems to be well tolerated, especially in patients with normal kidney function, and poses a low risk of hypoglycemia. The slight increase in LDL-C may prompt more aggressive lipid management. Whether blood pressure-lowering and weight loss will offset this increase in LDL-C is yet to be determined. Ongoing studies will help to further elucidate whether there is an increased risk of cardiovascular events.

Finally, canagliflozin distinguishes itself from other oral diabetes drugs by its added benefit of weight loss, an appealing side effect, especially in the growing population of obese individuals with type 2 diabetes mellitus.

Over the past decade, recommendations about the ideal glucose target in hospitalized diabetic patients have fluctuated. The controversy has extended to diabetic patients in various types of intensive care units and to those headed to the operating room. Although proposals exist on how to manage diabetes in the operating room, including intraoperative insulin infusions, outcomes probably depend more on how glucose is managed during the patient’s postoperative stay in the hospital. For patients who are less critically ill and less medically complex, continuous insulin infusions are used infrequently, and insulin is often prescribed by algorithm or, archaically, by some form of “catch-up” sliding scale. Studies indicate that even the fairly loose glucose target of 70 to 180 mg/dL is achieved consistently in only a few patients.¹

In view of a number of observations, including the link between hyperglycemia and postoperative wound infections, studies were designed to test the hypothesis that aggressively keeping glucose levels quite low in critically ill and postoperative diabetic patients would be beneficial. Instead, most of these studies found that overly tight glucose control in these settings led to untoward outcomes—and not only as the result of hypoglycemic episodes. Aiming for a modest serum glucose target of 150 to 200 mg/dL can significantly reduce the postoperative death rate, but the beneficial reduction is no greater if the target is less than 150 mg/dL.

With a looser glucose target, pre- and perioperative management of insulin-dependent diabetic patients can be simplified. Dobri and Lansang discuss the key practical principles of managing insulin before the patient goes to the operating suite. They emphasize relevant pearls of insulin physiology and discuss several scenarios we often encounter.

In fact, the principles they review are equally useful to remember when we admit diabetic patients to the hospital with orders to keep them “npo” while planning and awaiting tests or other procedures. A key take-home point is that severely insulinopenic patients require some exogenous basal insulin, even when not eating.

Over the past decade, recommendations about the ideal glucose target in hospitalized diabetic patients have fluctuated. The controversy has extended to diabetic patients in various types of intensive care units and to those headed to the operating room. Although proposals exist on how to manage diabetes in the operating room, including intraoperative insulin infusions, outcomes probably depend more on how glucose is managed during the patient’s postoperative stay in the hospital. For patients who are less critically ill and less medically complex, continuous insulin infusions are used infrequently, and insulin is often prescribed by algorithm or, archaically, by some form of “catch-up” sliding scale. Studies indicate that even the fairly loose glucose target of 70 to 180 mg/dL is achieved consistently in only a few patients.¹

In view of a number of observations, including the link between hyperglycemia and postoperative wound infections, studies were designed to test the hypothesis that aggressively keeping glucose levels quite low in critically ill and postoperative diabetic patients would be beneficial. Instead, most of these studies found that overly tight glucose control in these settings led to untoward outcomes—and not only as the result of hypoglycemic episodes. Aiming for a modest serum glucose target of 150 to 200 mg/dL can significantly reduce the postoperative death rate, but the beneficial reduction is no greater if the target is less than 150 mg/dL.

With a looser glucose target, pre- and perioperative management of insulin-dependent diabetic patients can be simplified. Dobri and Lansang discuss the key practical principles of managing insulin before the patient goes to the operating suite. They emphasize relevant pearls of insulin physiology and discuss several scenarios we often encounter.

In fact, the principles they review are equally useful to remember when we admit diabetic patients to the hospital with orders to keep them “npo” while planning and awaiting tests or other procedures. A key take-home point is that severely insulinopenic patients require some exogenous basal insulin, even when not eating.

Over the past decade, recommendations about the ideal glucose target in hospitalized diabetic patients have fluctuated. The controversy has extended to diabetic patients in various types of intensive care units and to those headed to the operating room. Although proposals exist on how to manage diabetes in the operating room, including intraoperative insulin infusions, outcomes probably depend more on how glucose is managed during the patient’s postoperative stay in the hospital. For patients who are less critically ill and less medically complex, continuous insulin infusions are used infrequently, and insulin is often prescribed by algorithm or, archaically, by some form of “catch-up” sliding scale. Studies indicate that even the fairly loose glucose target of 70 to 180 mg/dL is achieved consistently in only a few patients.¹

In view of a number of observations, including the link between hyperglycemia and postoperative wound infections, studies were designed to test the hypothesis that aggressively keeping glucose levels quite low in critically ill and postoperative diabetic patients would be beneficial. Instead, most of these studies found that overly tight glucose control in these settings led to untoward outcomes—and not only as the result of hypoglycemic episodes. Aiming for a modest serum glucose target of 150 to 200 mg/dL can significantly reduce the postoperative death rate, but the beneficial reduction is no greater if the target is less than 150 mg/dL.

With a looser glucose target, pre- and perioperative management of insulin-dependent diabetic patients can be simplified. Dobri and Lansang discuss the key practical principles of managing insulin before the patient goes to the operating suite. They emphasize relevant pearls of insulin physiology and discuss several scenarios we often encounter.

In fact, the principles they review are equally useful to remember when we admit diabetic patients to the hospital with orders to keep them “npo” while planning and awaiting tests or other procedures. A key take-home point is that severely insulinopenic patients require some exogenous basal insulin, even when not eating.

Continuing at least part of the basal insulin is the reasonable, physiologic approach to controlling glucose levels before surgery in patients with diabetes. The process involves three basic steps:

• Ascertaining the type of diabetes
• Adjusting the basal insulin dosage
• Stopping the prandial insulin.

The steps are the same whether the surgery is major or minor. These recommendations are based on general principles of insulin action, data from large databases of surgical inpatients, and expert clinical experience translated into standardized protocols.^1,2

WHY CONTINUE THE INSULIN?

Stopping or decreasing insulin because of a fear of hypoglycemia is not appropriate, as the resulting hyperglycemia can lead to delayed wound healing, wound infection, fluid and electrolyte shifts, diabetic ketoacidosis, and hyperosmolar states.

Insulin inhibits both gluconeogenesis and conversion of glycogen to glucose, processes that occur regardless of food intake. It also inhibits degradation of fats to fatty acids and of fatty acids to ketones. This is why inadequate insulin dosing can lead to uncontrolled hyperglycemia and even ketoacidosis, and thus why long-acting insulin is needed in a fasting state.

STEP 1: ASCERTAIN THE TYPE OF DIABETES

Does the patient have type 1 or type 2 diabetes, and does that even matter?

The type of diabetes should not matter, since ideally the insulin should be dosed the same for both types. However, the consequences of inappropriate insulin management may be different.

Usually, the type of diabetes can be ascertained by the history. If the patient was diagnosed at age 40 or later and was on oral medication for years before insulin was started, then he or she most likely has type 2. If the patient was younger than 40 at the time of diagnosis, was lean, and was started on insulin within a year of diagnosis, then he or she likely has type 1.

If this information is not available or is unreliable and the patient has been on insulin for many years, we recommend viewing the patient as being insulinopenic, ie, not producing enough insulin endogenously and thus requiring insulin at all times.

Though checking for antibody markers of type 1 diabetes might give a more definitive answer, it is not practical before surgery.

In the setting of surgical stress, withholding the basal insulin preoperatively and just giving a small dose of fast-acting (see Table 1 for the different classes of insulin) or shortacting insulin as part of a sliding scale (ie, insulin given only when the blood glucose reaches a certain high level) can send a patient with type 1 diabetes into diabetic ketoacidosis by the end of the day. This is less likely to occur in a patient with type 2 diabetes with some endogenous insulin secretion.

STEP 2: ADJUST THE BASAL INSULIN

Basal insulin is the insulin that the healthy person’s body produces when fasting. For a diabetic patient already on insulin, basal insulin is insulin injected to prevent ketogenesis, glycogenolysis, and gluconeogenesis in the fasting state.

If the basal insulin is long-acting

Long-acting insulins have a relatively peakless profile and, when properly dosed, should not result in hypoglycemia when a patient is fasting.

Preoperatively, the patient should take it as close as possible to the usual time of injection. This could be at home either at bedtime the night before surgery or the morning of surgery. If there is concern for hypoglycemia, the injection can be given when the patient is at the hospital.

• If the patient does not tend to have hypoglycemic episodes and the total daily basal insulin dose is roughly the same as the total daily mealtime (prandial) dose (eg, 50% basal, 50% prandial ratio), the full dose of basal insulin can be given.³

Example: If the patient is on insulin glargine 30 U at bedtime and insulin lispro 10 U with each meal and does not have hypoglycemic episodes, then insulin glargine 30 U should be taken at bedtime.

• If the patient has hypoglycemic episodes at home, then the basal insulin can be reduced by 25%.³

Example: If the patient is on insulin glargine 30 U at bedtime and insulin glulisine 10 U with each meal (appropriate proportion of doses, similar to the example above) but has hypoglycemic episodes at home on this regimen, then only 22 U of insulin glargine should be taken at bedtime.

• If the patient’s regimen has disproportionately more basal insulin than mealtime insulin, then the total daily doses can be added and half can be given as the basal insulin.

Example: If the patient is on insulin detemir 30 U every morning at 6 am and insulin aspart 6 U with each meal and has no hypoglycemic episodes, then 24 U of insulin detemir should be taken in the morning (ie, half of the total of 30 + 6 + 6 + 6).

• In the less common scenario of diabetes managed only with basal insulin (no other diabetes injections or oral agents), then half of the dose can be given.
• If the patient is on twice-daily long-acting basal insulin, then both the dose the night before surgery and the dose the morning of surgery should be adjusted.

The intermediate-acting insulin neutral protamine Hagedorn (NPH) is usually given twice a day because of its profile (Table 1).

• On the night before surgery, the full dose of NPH insulin should be taken, unless the patient will now skip a nighttime meal because of taking nothing by mouth, in which case the dose can be decreased by 25%.¹
• On the morning of surgery, since the patient will be skipping breakfast and probably also lunch, the dose should be reduced by 50%.^3,4

Special situation: Premixed insulins

Premixed insulins (70/30, 75/25) are a combination of intermediate-acting insulin and either fast-acting or short-acting insulin. In other words, they are combinations of basal and prandial insulin. Their use is thus not ideal in the preoperative period. There are two options in these situations.

One option is to switch to a regimen that includes long-acting insulin. If the patient is admitted for surgery, then the hospital staff can change the insulin regimen to long-acting basal insulin. A quick formula for conversion is to add all the premixed insulin doses and give half as basal insulin on the morning of surgery, similar to the scenario above for the patient with long-acting basal insulin that was out of proportion to the prandial insulin injections.

For example, if the usual regimen is insulin 70/30 NPH/Regular, 60 U with breakfast, 30 U with dinner, then the patient can take 45 U of insulin glargine (which is half of 60 + 30) in the morning or evening before surgery.

Another option is to adjust the dose of pre-mixed insulin. Sometimes it is not feasible or economical to change the patient’s premixed insulin just before surgery. In these situations, the patient can take half of the morning dose, followed by dextrose-containing intravenous fluids and blood glucose checks.

We recommend preoperatively giving at least part of the patient’s previous basal insulin, regardless of the type of diabetes, the type of surgery, or the fasting period.

STEP 3: STOP THE PRANDIAL INSULIN

Prandial insulin—given before each meal to cover the carbohydrates to be consumed—should be stopped the morning of surgery.^3,4

WHAT ABOUT SLIDING SCALE INSULIN?

Using a sliding scale alone has no known benefit. Although it can be a quick fix to correct a high glucose level, it should be added to the basal insulin and not used as the sole insulin therapy. If a sliding scale is used, fast-acting insulin (aspart, glulisine, lispro) is preferred over regular insulin because of the more rapid onset and shorter duration of action.

Patients already using a supplemental insulin scale can apply it to correct a blood glucose above 200 mg/dL on the morning of surgery.

MAINTENANCE FLUIDS

As long as glucose levels are not very elevated (ie, > 200 mg/dL), after 12 hours on a nothing-by-mouth regimen, provide dextrose in the IV fluid to prevent hypoglycemia (eg, the patient received long-acting insulin and the glucose levels are running low) or to prevent starvation ketosis, which may result in ketones in the blood or urine. We recommend 5% dextrose in half-normal (0.45%) saline at 50 to 75 mL/hour as maintenance fluid; the infusion rate should be lower if fluid overload is a concern.

POSTOPERATIVE INSULIN MANAGEMENT

Once patients are discharged and can go back to their previous routine, they can restart their usual insulin regimen the same evening. The prandial insulin will be resumed when the regular diet is reintroduced, and the doses will be adjusted according to food intake.

Continuing at least part of the basal insulin is the reasonable, physiologic approach to controlling glucose levels before surgery in patients with diabetes. The process involves three basic steps:

• Ascertaining the type of diabetes
• Adjusting the basal insulin dosage
• Stopping the prandial insulin.

The steps are the same whether the surgery is major or minor. These recommendations are based on general principles of insulin action, data from large databases of surgical inpatients, and expert clinical experience translated into standardized protocols.^1,2

WHY CONTINUE THE INSULIN?

Stopping or decreasing insulin because of a fear of hypoglycemia is not appropriate, as the resulting hyperglycemia can lead to delayed wound healing, wound infection, fluid and electrolyte shifts, diabetic ketoacidosis, and hyperosmolar states.

Insulin inhibits both gluconeogenesis and conversion of glycogen to glucose, processes that occur regardless of food intake. It also inhibits degradation of fats to fatty acids and of fatty acids to ketones. This is why inadequate insulin dosing can lead to uncontrolled hyperglycemia and even ketoacidosis, and thus why long-acting insulin is needed in a fasting state.

STEP 1: ASCERTAIN THE TYPE OF DIABETES

Does the patient have type 1 or type 2 diabetes, and does that even matter?

The type of diabetes should not matter, since ideally the insulin should be dosed the same for both types. However, the consequences of inappropriate insulin management may be different.

Usually, the type of diabetes can be ascertained by the history. If the patient was diagnosed at age 40 or later and was on oral medication for years before insulin was started, then he or she most likely has type 2. If the patient was younger than 40 at the time of diagnosis, was lean, and was started on insulin within a year of diagnosis, then he or she likely has type 1.

If this information is not available or is unreliable and the patient has been on insulin for many years, we recommend viewing the patient as being insulinopenic, ie, not producing enough insulin endogenously and thus requiring insulin at all times.

Though checking for antibody markers of type 1 diabetes might give a more definitive answer, it is not practical before surgery.

In the setting of surgical stress, withholding the basal insulin preoperatively and just giving a small dose of fast-acting (see Table 1 for the different classes of insulin) or shortacting insulin as part of a sliding scale (ie, insulin given only when the blood glucose reaches a certain high level) can send a patient with type 1 diabetes into diabetic ketoacidosis by the end of the day. This is less likely to occur in a patient with type 2 diabetes with some endogenous insulin secretion.

STEP 2: ADJUST THE BASAL INSULIN

Basal insulin is the insulin that the healthy person’s body produces when fasting. For a diabetic patient already on insulin, basal insulin is insulin injected to prevent ketogenesis, glycogenolysis, and gluconeogenesis in the fasting state.

If the basal insulin is long-acting

Long-acting insulins have a relatively peakless profile and, when properly dosed, should not result in hypoglycemia when a patient is fasting.

Preoperatively, the patient should take it as close as possible to the usual time of injection. This could be at home either at bedtime the night before surgery or the morning of surgery. If there is concern for hypoglycemia, the injection can be given when the patient is at the hospital.

• If the patient does not tend to have hypoglycemic episodes and the total daily basal insulin dose is roughly the same as the total daily mealtime (prandial) dose (eg, 50% basal, 50% prandial ratio), the full dose of basal insulin can be given.³

Example: If the patient is on insulin glargine 30 U at bedtime and insulin lispro 10 U with each meal and does not have hypoglycemic episodes, then insulin glargine 30 U should be taken at bedtime.

• If the patient has hypoglycemic episodes at home, then the basal insulin can be reduced by 25%.³

Example: If the patient is on insulin glargine 30 U at bedtime and insulin glulisine 10 U with each meal (appropriate proportion of doses, similar to the example above) but has hypoglycemic episodes at home on this regimen, then only 22 U of insulin glargine should be taken at bedtime.

• If the patient’s regimen has disproportionately more basal insulin than mealtime insulin, then the total daily doses can be added and half can be given as the basal insulin.

Example: If the patient is on insulin detemir 30 U every morning at 6 am and insulin aspart 6 U with each meal and has no hypoglycemic episodes, then 24 U of insulin detemir should be taken in the morning (ie, half of the total of 30 + 6 + 6 + 6).

• In the less common scenario of diabetes managed only with basal insulin (no other diabetes injections or oral agents), then half of the dose can be given.
• If the patient is on twice-daily long-acting basal insulin, then both the dose the night before surgery and the dose the morning of surgery should be adjusted.

The intermediate-acting insulin neutral protamine Hagedorn (NPH) is usually given twice a day because of its profile (Table 1).

• On the night before surgery, the full dose of NPH insulin should be taken, unless the patient will now skip a nighttime meal because of taking nothing by mouth, in which case the dose can be decreased by 25%.¹
• On the morning of surgery, since the patient will be skipping breakfast and probably also lunch, the dose should be reduced by 50%.^3,4

Special situation: Premixed insulins

Premixed insulins (70/30, 75/25) are a combination of intermediate-acting insulin and either fast-acting or short-acting insulin. In other words, they are combinations of basal and prandial insulin. Their use is thus not ideal in the preoperative period. There are two options in these situations.

One option is to switch to a regimen that includes long-acting insulin. If the patient is admitted for surgery, then the hospital staff can change the insulin regimen to long-acting basal insulin. A quick formula for conversion is to add all the premixed insulin doses and give half as basal insulin on the morning of surgery, similar to the scenario above for the patient with long-acting basal insulin that was out of proportion to the prandial insulin injections.

For example, if the usual regimen is insulin 70/30 NPH/Regular, 60 U with breakfast, 30 U with dinner, then the patient can take 45 U of insulin glargine (which is half of 60 + 30) in the morning or evening before surgery.

Another option is to adjust the dose of pre-mixed insulin. Sometimes it is not feasible or economical to change the patient’s premixed insulin just before surgery. In these situations, the patient can take half of the morning dose, followed by dextrose-containing intravenous fluids and blood glucose checks.

We recommend preoperatively giving at least part of the patient’s previous basal insulin, regardless of the type of diabetes, the type of surgery, or the fasting period.

STEP 3: STOP THE PRANDIAL INSULIN

Prandial insulin—given before each meal to cover the carbohydrates to be consumed—should be stopped the morning of surgery.^3,4

WHAT ABOUT SLIDING SCALE INSULIN?

Using a sliding scale alone has no known benefit. Although it can be a quick fix to correct a high glucose level, it should be added to the basal insulin and not used as the sole insulin therapy. If a sliding scale is used, fast-acting insulin (aspart, glulisine, lispro) is preferred over regular insulin because of the more rapid onset and shorter duration of action.

Patients already using a supplemental insulin scale can apply it to correct a blood glucose above 200 mg/dL on the morning of surgery.

MAINTENANCE FLUIDS

As long as glucose levels are not very elevated (ie, > 200 mg/dL), after 12 hours on a nothing-by-mouth regimen, provide dextrose in the IV fluid to prevent hypoglycemia (eg, the patient received long-acting insulin and the glucose levels are running low) or to prevent starvation ketosis, which may result in ketones in the blood or urine. We recommend 5% dextrose in half-normal (0.45%) saline at 50 to 75 mL/hour as maintenance fluid; the infusion rate should be lower if fluid overload is a concern.

POSTOPERATIVE INSULIN MANAGEMENT

Once patients are discharged and can go back to their previous routine, they can restart their usual insulin regimen the same evening. The prandial insulin will be resumed when the regular diet is reintroduced, and the doses will be adjusted according to food intake.

Continuing at least part of the basal insulin is the reasonable, physiologic approach to controlling glucose levels before surgery in patients with diabetes. The process involves three basic steps:

• Ascertaining the type of diabetes
• Adjusting the basal insulin dosage
• Stopping the prandial insulin.

The steps are the same whether the surgery is major or minor. These recommendations are based on general principles of insulin action, data from large databases of surgical inpatients, and expert clinical experience translated into standardized protocols.^1,2

WHY CONTINUE THE INSULIN?

Stopping or decreasing insulin because of a fear of hypoglycemia is not appropriate, as the resulting hyperglycemia can lead to delayed wound healing, wound infection, fluid and electrolyte shifts, diabetic ketoacidosis, and hyperosmolar states.

Insulin inhibits both gluconeogenesis and conversion of glycogen to glucose, processes that occur regardless of food intake. It also inhibits degradation of fats to fatty acids and of fatty acids to ketones. This is why inadequate insulin dosing can lead to uncontrolled hyperglycemia and even ketoacidosis, and thus why long-acting insulin is needed in a fasting state.

STEP 1: ASCERTAIN THE TYPE OF DIABETES

Does the patient have type 1 or type 2 diabetes, and does that even matter?

The type of diabetes should not matter, since ideally the insulin should be dosed the same for both types. However, the consequences of inappropriate insulin management may be different.

Usually, the type of diabetes can be ascertained by the history. If the patient was diagnosed at age 40 or later and was on oral medication for years before insulin was started, then he or she most likely has type 2. If the patient was younger than 40 at the time of diagnosis, was lean, and was started on insulin within a year of diagnosis, then he or she likely has type 1.

If this information is not available or is unreliable and the patient has been on insulin for many years, we recommend viewing the patient as being insulinopenic, ie, not producing enough insulin endogenously and thus requiring insulin at all times.

Though checking for antibody markers of type 1 diabetes might give a more definitive answer, it is not practical before surgery.

In the setting of surgical stress, withholding the basal insulin preoperatively and just giving a small dose of fast-acting (see Table 1 for the different classes of insulin) or shortacting insulin as part of a sliding scale (ie, insulin given only when the blood glucose reaches a certain high level) can send a patient with type 1 diabetes into diabetic ketoacidosis by the end of the day. This is less likely to occur in a patient with type 2 diabetes with some endogenous insulin secretion.

STEP 2: ADJUST THE BASAL INSULIN

Basal insulin is the insulin that the healthy person’s body produces when fasting. For a diabetic patient already on insulin, basal insulin is insulin injected to prevent ketogenesis, glycogenolysis, and gluconeogenesis in the fasting state.

If the basal insulin is long-acting

Long-acting insulins have a relatively peakless profile and, when properly dosed, should not result in hypoglycemia when a patient is fasting.

Preoperatively, the patient should take it as close as possible to the usual time of injection. This could be at home either at bedtime the night before surgery or the morning of surgery. If there is concern for hypoglycemia, the injection can be given when the patient is at the hospital.

• If the patient does not tend to have hypoglycemic episodes and the total daily basal insulin dose is roughly the same as the total daily mealtime (prandial) dose (eg, 50% basal, 50% prandial ratio), the full dose of basal insulin can be given.³

Example: If the patient is on insulin glargine 30 U at bedtime and insulin lispro 10 U with each meal and does not have hypoglycemic episodes, then insulin glargine 30 U should be taken at bedtime.

• If the patient has hypoglycemic episodes at home, then the basal insulin can be reduced by 25%.³

Example: If the patient is on insulin glargine 30 U at bedtime and insulin glulisine 10 U with each meal (appropriate proportion of doses, similar to the example above) but has hypoglycemic episodes at home on this regimen, then only 22 U of insulin glargine should be taken at bedtime.

• If the patient’s regimen has disproportionately more basal insulin than mealtime insulin, then the total daily doses can be added and half can be given as the basal insulin.

Example: If the patient is on insulin detemir 30 U every morning at 6 am and insulin aspart 6 U with each meal and has no hypoglycemic episodes, then 24 U of insulin detemir should be taken in the morning (ie, half of the total of 30 + 6 + 6 + 6).

• In the less common scenario of diabetes managed only with basal insulin (no other diabetes injections or oral agents), then half of the dose can be given.
• If the patient is on twice-daily long-acting basal insulin, then both the dose the night before surgery and the dose the morning of surgery should be adjusted.

The intermediate-acting insulin neutral protamine Hagedorn (NPH) is usually given twice a day because of its profile (Table 1).

• On the night before surgery, the full dose of NPH insulin should be taken, unless the patient will now skip a nighttime meal because of taking nothing by mouth, in which case the dose can be decreased by 25%.¹
• On the morning of surgery, since the patient will be skipping breakfast and probably also lunch, the dose should be reduced by 50%.^3,4

Special situation: Premixed insulins

Premixed insulins (70/30, 75/25) are a combination of intermediate-acting insulin and either fast-acting or short-acting insulin. In other words, they are combinations of basal and prandial insulin. Their use is thus not ideal in the preoperative period. There are two options in these situations.

One option is to switch to a regimen that includes long-acting insulin. If the patient is admitted for surgery, then the hospital staff can change the insulin regimen to long-acting basal insulin. A quick formula for conversion is to add all the premixed insulin doses and give half as basal insulin on the morning of surgery, similar to the scenario above for the patient with long-acting basal insulin that was out of proportion to the prandial insulin injections.

For example, if the usual regimen is insulin 70/30 NPH/Regular, 60 U with breakfast, 30 U with dinner, then the patient can take 45 U of insulin glargine (which is half of 60 + 30) in the morning or evening before surgery.

Another option is to adjust the dose of pre-mixed insulin. Sometimes it is not feasible or economical to change the patient’s premixed insulin just before surgery. In these situations, the patient can take half of the morning dose, followed by dextrose-containing intravenous fluids and blood glucose checks.

We recommend preoperatively giving at least part of the patient’s previous basal insulin, regardless of the type of diabetes, the type of surgery, or the fasting period.

STEP 3: STOP THE PRANDIAL INSULIN

Prandial insulin—given before each meal to cover the carbohydrates to be consumed—should be stopped the morning of surgery.^3,4

WHAT ABOUT SLIDING SCALE INSULIN?

Using a sliding scale alone has no known benefit. Although it can be a quick fix to correct a high glucose level, it should be added to the basal insulin and not used as the sole insulin therapy. If a sliding scale is used, fast-acting insulin (aspart, glulisine, lispro) is preferred over regular insulin because of the more rapid onset and shorter duration of action.

Patients already using a supplemental insulin scale can apply it to correct a blood glucose above 200 mg/dL on the morning of surgery.

MAINTENANCE FLUIDS

As long as glucose levels are not very elevated (ie, > 200 mg/dL), after 12 hours on a nothing-by-mouth regimen, provide dextrose in the IV fluid to prevent hypoglycemia (eg, the patient received long-acting insulin and the glucose levels are running low) or to prevent starvation ketosis, which may result in ketones in the blood or urine. We recommend 5% dextrose in half-normal (0.45%) saline at 50 to 75 mL/hour as maintenance fluid; the infusion rate should be lower if fluid overload is a concern.

POSTOPERATIVE INSULIN MANAGEMENT

Once patients are discharged and can go back to their previous routine, they can restart their usual insulin regimen the same evening. The prandial insulin will be resumed when the regular diet is reintroduced, and the doses will be adjusted according to food intake.

Peter A. Holt, MD
Associate Professor of Medicine
The Johns Hopkins University School of Medicine
Baltimore, Maryland

Tuna Ozyurekoglu, MD
Christine M. Kleinert Institute for Hand and Microsurgery
Louisville, Kentucky

Shaili Deveshwar, MD
Sports Medicine and Orthopedic Center
Greensboro, North Carolina 

Edmund J. MacLaughlin, MD 
Cambridge, Maryland

Shirley W. Pang, MD
St. Jude Heritage Medical Group
Fullerton, California

Jack S. Tuber, DO 
SunValley Arthritis Center
Peoria, Arizona

Joy Schechtman, DO 
SunValley Arthritis CenterPeoria, Arizona

Thomas M. Zizic, MD
Associate Professor of Medicine
The Johns Hopkins University School of Medicine
Baltimore, Maryland

Peter A. Holt, MD
Associate Professor of Medicine
The Johns Hopkins University School of Medicine
Baltimore, Maryland

Tuna Ozyurekoglu, MD
Christine M. Kleinert Institute for Hand and Microsurgery
Louisville, Kentucky

Shaili Deveshwar, MD
Sports Medicine and Orthopedic Center
Greensboro, North Carolina 

Edmund J. MacLaughlin, MD 
Cambridge, Maryland

Shirley W. Pang, MD
St. Jude Heritage Medical Group
Fullerton, California

Jack S. Tuber, DO 
SunValley Arthritis Center
Peoria, Arizona

Joy Schechtman, DO 
SunValley Arthritis CenterPeoria, Arizona

Thomas M. Zizic, MD
Associate Professor of Medicine
The Johns Hopkins University School of Medicine
Baltimore, Maryland

Peter A. Holt, MD
Associate Professor of Medicine
The Johns Hopkins University School of Medicine
Baltimore, Maryland

Tuna Ozyurekoglu, MD
Christine M. Kleinert Institute for Hand and Microsurgery
Louisville, Kentucky

Shaili Deveshwar, MD
Sports Medicine and Orthopedic Center
Greensboro, North Carolina 

Edmund J. MacLaughlin, MD 
Cambridge, Maryland

Shirley W. Pang, MD
St. Jude Heritage Medical Group
Fullerton, California

Jack S. Tuber, DO 
SunValley Arthritis Center
Peoria, Arizona

Joy Schechtman, DO 
SunValley Arthritis CenterPeoria, Arizona

Thomas M. Zizic, MD
Associate Professor of Medicine
The Johns Hopkins University School of Medicine
Baltimore, Maryland

In his book, How We Do Harm: A Doctor Breaks Ranks About Being Sick in America, Otis Brawley¹ writes, “I believe that a man should know what we know, what we don’t know, and what we believe about prostate cancer. I have been concerned that many patients and physicians have confused what is believed with what is known.” I agree.

Common sense is what we believe. Does common sense trump science? Did the US Preventive Services Task Force (USPSTF) get it wrong? I don’t think so.

The USPSTF bases its recommendations on an explicit assessment of the science that informs us of the benefits and harms of a preventive service, and a judgment about the magnitude of net benefit.

So what do we know about the benefits of prostate cancer screening? When attempting to answer the question of whether an intervention is beneficial, there is a hierarchy of evidence, from most likely to be wrong to most likely to be right. Relying on our personal stories is the former; relying on well-conducted randomized trials is the latter.

We do an enormous disservice to our patients if we pretend that this is just a blood test. Men will get biopsies and there will be complications.In the multicenter Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial² conducted in the United States, there was a nonsignificant increase in prostate-cancer mortality in the screening group, while the European Randomized Study of Screening for Prostate Cancer (ERSPC)³ trial showed a statistically significant absolute reduction of 0.10 prostate-cancer deaths per 1000 person-years after a median follow-up of 11 years. In the ERSPC trial, all-cause mortality was 19.1% in the screened group and 19.3% in the control group, a difference that was not significant. What we know is that after 10 years, even with aggressive treatment of 80% to 90% of screen-detected cancers, very few, if any, men will have lived longer because they were screened.

What don’t we know about the benefits? We don’t know whether following screened and nonscreened men for 15 or 20 years or longer will demonstrate a larger difference in mortality. Competing causes of mortality make it progressively less likely that men who are screened will actually live longer. The average age of death from prostate cancer is 80 years, and 70% of all deaths occur after age 75.⁴ Contrast those statistics to breast cancer, for which the average age of death is 68 years and 63% of all deaths occur before age 75.⁵

What do we believe about the benefits? Some certainly believe the trials must be wrong; common sense tells us that early detection and treatment must provide more benefit than what the evidence has shown. Common sense tells us that the decline in prostate cancer mortality over the past 2 decades must be due to screening, although the ERSPC results clearly show that neither the magnitude nor the timing of the decline can be attributed to screening.

What do we know—and not know—about the harms?

We know that much of the suffering from prostate cancer is a consequence of the diagnosis and management of the disease, rather than the disease itself. Complications of both diagnosis and treatment of prostate cancer are frequent and serious.⁶ We also know that many screen-detected cancers would never become apparent in a man’s lifetime without screening.

We don’t know the precise magnitude of overdiagnosis, although all estimates suggest it is substantial. In the ERSPC trial, 9.6% of the screened group received a prostate cancer diagnosis, vs 6.0% of the control group—a 60% increase in the rate of diagnosis. The recently published long-term results from the Prostate Cancer Prevention Trial⁷ are enlightening. Finasteride reduced the incidence of screen-detected cancers by 30%, with no impact on all-cause mortality at 18 years. If those screen-detected cancers had been a significant threat to health, then after 18 years we would have expected some mortality benefit from finasteride.

What do we believe about the harms of screening?
We believe that by being more conservative about who gets treated, we shift the balance of benefits and harms of screening. There is no question that reducing the burden of overdiagnosis and overtreatment would provide a welcome reduction in the harms. But can we do it?⁸

In the United States 90% of men found to have prostate cancer are treated (including about 75% of men with low-risk cancers).⁶ And although we hope to be able to reduce harms without changing benefits, we do not know what impact more conservative management of screen-detected cancers would have on the already small effect of screening on prostate cancer mortality.

So what is the balance of benefit and harms? Should we make that judgment on what we know, or on what we believe?

Science trumps common sense. For every 1000 men screened, at most, one will avoid a prostate cancer death at 10 years. But 30 to 40 will have erectile dysfunction, urinary incontinence, or both due to treatment, 2 men will experience a serious cardiovascular event, one will have a venous thromboembolic event, and one in 3000 screened will die from complications of surgical treatment.⁶

The USPSTF concluded that the benefits of PSA screening do not outweigh the harms, but acknowledged that shared decision making is still appropriate when a physician feels obliged to offer the test or a patient requests it.

What does shared decision making look like? Just offering screening and answering any questions is not good enough. We do an enormous disservice to our patients if we pretend that this is just a blood test and that we can decide later what to do with the information. Men will get biopsies and there will be complications. Cancer will be detected, and men will be treated, many unnecessarily.

Routine screening for prostate cancer in the absence of a truly formed decision is unacceptable.We need to tell our patients that the likelihood of avoiding a prostate cancer death over 10 years as a result of regular PSA screening is at most very small, and that many more men will suffer the harms of unnecessary treatment than will benefit. A few will die prematurely as a result of the complications of treating a screen-detected cancer.

If, with this knowledge, a patient places a higher value on the possibility of avoiding a prostate cancer death than he does on the known harms of diagnosis and treatment, he can still decide to be screened. He has made an informed decision. However, routine screening for prostate cancer in the absence of a truly informed decision is unacceptable.

In his book, How We Do Harm: A Doctor Breaks Ranks About Being Sick in America, Otis Brawley¹ writes, “I believe that a man should know what we know, what we don’t know, and what we believe about prostate cancer. I have been concerned that many patients and physicians have confused what is believed with what is known.” I agree.

Common sense is what we believe. Does common sense trump science? Did the US Preventive Services Task Force (USPSTF) get it wrong? I don’t think so.

The USPSTF bases its recommendations on an explicit assessment of the science that informs us of the benefits and harms of a preventive service, and a judgment about the magnitude of net benefit.

So what do we know about the benefits of prostate cancer screening? When attempting to answer the question of whether an intervention is beneficial, there is a hierarchy of evidence, from most likely to be wrong to most likely to be right. Relying on our personal stories is the former; relying on well-conducted randomized trials is the latter.

We do an enormous disservice to our patients if we pretend that this is just a blood test. Men will get biopsies and there will be complications.In the multicenter Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial² conducted in the United States, there was a nonsignificant increase in prostate-cancer mortality in the screening group, while the European Randomized Study of Screening for Prostate Cancer (ERSPC)³ trial showed a statistically significant absolute reduction of 0.10 prostate-cancer deaths per 1000 person-years after a median follow-up of 11 years. In the ERSPC trial, all-cause mortality was 19.1% in the screened group and 19.3% in the control group, a difference that was not significant. What we know is that after 10 years, even with aggressive treatment of 80% to 90% of screen-detected cancers, very few, if any, men will have lived longer because they were screened.

What don’t we know about the benefits? We don’t know whether following screened and nonscreened men for 15 or 20 years or longer will demonstrate a larger difference in mortality. Competing causes of mortality make it progressively less likely that men who are screened will actually live longer. The average age of death from prostate cancer is 80 years, and 70% of all deaths occur after age 75.⁴ Contrast those statistics to breast cancer, for which the average age of death is 68 years and 63% of all deaths occur before age 75.⁵

What do we believe about the benefits? Some certainly believe the trials must be wrong; common sense tells us that early detection and treatment must provide more benefit than what the evidence has shown. Common sense tells us that the decline in prostate cancer mortality over the past 2 decades must be due to screening, although the ERSPC results clearly show that neither the magnitude nor the timing of the decline can be attributed to screening.

What do we know—and not know—about the harms?

We know that much of the suffering from prostate cancer is a consequence of the diagnosis and management of the disease, rather than the disease itself. Complications of both diagnosis and treatment of prostate cancer are frequent and serious.⁶ We also know that many screen-detected cancers would never become apparent in a man’s lifetime without screening.

We don’t know the precise magnitude of overdiagnosis, although all estimates suggest it is substantial. In the ERSPC trial, 9.6% of the screened group received a prostate cancer diagnosis, vs 6.0% of the control group—a 60% increase in the rate of diagnosis. The recently published long-term results from the Prostate Cancer Prevention Trial⁷ are enlightening. Finasteride reduced the incidence of screen-detected cancers by 30%, with no impact on all-cause mortality at 18 years. If those screen-detected cancers had been a significant threat to health, then after 18 years we would have expected some mortality benefit from finasteride.

What do we believe about the harms of screening?
We believe that by being more conservative about who gets treated, we shift the balance of benefits and harms of screening. There is no question that reducing the burden of overdiagnosis and overtreatment would provide a welcome reduction in the harms. But can we do it?⁸

In the United States 90% of men found to have prostate cancer are treated (including about 75% of men with low-risk cancers).⁶ And although we hope to be able to reduce harms without changing benefits, we do not know what impact more conservative management of screen-detected cancers would have on the already small effect of screening on prostate cancer mortality.

So what is the balance of benefit and harms? Should we make that judgment on what we know, or on what we believe?

Science trumps common sense. For every 1000 men screened, at most, one will avoid a prostate cancer death at 10 years. But 30 to 40 will have erectile dysfunction, urinary incontinence, or both due to treatment, 2 men will experience a serious cardiovascular event, one will have a venous thromboembolic event, and one in 3000 screened will die from complications of surgical treatment.⁶

The USPSTF concluded that the benefits of PSA screening do not outweigh the harms, but acknowledged that shared decision making is still appropriate when a physician feels obliged to offer the test or a patient requests it.

What does shared decision making look like? Just offering screening and answering any questions is not good enough. We do an enormous disservice to our patients if we pretend that this is just a blood test and that we can decide later what to do with the information. Men will get biopsies and there will be complications. Cancer will be detected, and men will be treated, many unnecessarily.

Routine screening for prostate cancer in the absence of a truly formed decision is unacceptable.We need to tell our patients that the likelihood of avoiding a prostate cancer death over 10 years as a result of regular PSA screening is at most very small, and that many more men will suffer the harms of unnecessary treatment than will benefit. A few will die prematurely as a result of the complications of treating a screen-detected cancer.

If, with this knowledge, a patient places a higher value on the possibility of avoiding a prostate cancer death than he does on the known harms of diagnosis and treatment, he can still decide to be screened. He has made an informed decision. However, routine screening for prostate cancer in the absence of a truly informed decision is unacceptable.

In his book, How We Do Harm: A Doctor Breaks Ranks About Being Sick in America, Otis Brawley¹ writes, “I believe that a man should know what we know, what we don’t know, and what we believe about prostate cancer. I have been concerned that many patients and physicians have confused what is believed with what is known.” I agree.

Common sense is what we believe. Does common sense trump science? Did the US Preventive Services Task Force (USPSTF) get it wrong? I don’t think so.

The USPSTF bases its recommendations on an explicit assessment of the science that informs us of the benefits and harms of a preventive service, and a judgment about the magnitude of net benefit.

So what do we know about the benefits of prostate cancer screening? When attempting to answer the question of whether an intervention is beneficial, there is a hierarchy of evidence, from most likely to be wrong to most likely to be right. Relying on our personal stories is the former; relying on well-conducted randomized trials is the latter.

We do an enormous disservice to our patients if we pretend that this is just a blood test. Men will get biopsies and there will be complications.In the multicenter Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial² conducted in the United States, there was a nonsignificant increase in prostate-cancer mortality in the screening group, while the European Randomized Study of Screening for Prostate Cancer (ERSPC)³ trial showed a statistically significant absolute reduction of 0.10 prostate-cancer deaths per 1000 person-years after a median follow-up of 11 years. In the ERSPC trial, all-cause mortality was 19.1% in the screened group and 19.3% in the control group, a difference that was not significant. What we know is that after 10 years, even with aggressive treatment of 80% to 90% of screen-detected cancers, very few, if any, men will have lived longer because they were screened.

What don’t we know about the benefits? We don’t know whether following screened and nonscreened men for 15 or 20 years or longer will demonstrate a larger difference in mortality. Competing causes of mortality make it progressively less likely that men who are screened will actually live longer. The average age of death from prostate cancer is 80 years, and 70% of all deaths occur after age 75.⁴ Contrast those statistics to breast cancer, for which the average age of death is 68 years and 63% of all deaths occur before age 75.⁵

What do we believe about the benefits? Some certainly believe the trials must be wrong; common sense tells us that early detection and treatment must provide more benefit than what the evidence has shown. Common sense tells us that the decline in prostate cancer mortality over the past 2 decades must be due to screening, although the ERSPC results clearly show that neither the magnitude nor the timing of the decline can be attributed to screening.

What do we know—and not know—about the harms?

We know that much of the suffering from prostate cancer is a consequence of the diagnosis and management of the disease, rather than the disease itself. Complications of both diagnosis and treatment of prostate cancer are frequent and serious.⁶ We also know that many screen-detected cancers would never become apparent in a man’s lifetime without screening.

We don’t know the precise magnitude of overdiagnosis, although all estimates suggest it is substantial. In the ERSPC trial, 9.6% of the screened group received a prostate cancer diagnosis, vs 6.0% of the control group—a 60% increase in the rate of diagnosis. The recently published long-term results from the Prostate Cancer Prevention Trial⁷ are enlightening. Finasteride reduced the incidence of screen-detected cancers by 30%, with no impact on all-cause mortality at 18 years. If those screen-detected cancers had been a significant threat to health, then after 18 years we would have expected some mortality benefit from finasteride.

What do we believe about the harms of screening?
We believe that by being more conservative about who gets treated, we shift the balance of benefits and harms of screening. There is no question that reducing the burden of overdiagnosis and overtreatment would provide a welcome reduction in the harms. But can we do it?⁸

In the United States 90% of men found to have prostate cancer are treated (including about 75% of men with low-risk cancers).⁶ And although we hope to be able to reduce harms without changing benefits, we do not know what impact more conservative management of screen-detected cancers would have on the already small effect of screening on prostate cancer mortality.

So what is the balance of benefit and harms? Should we make that judgment on what we know, or on what we believe?

Science trumps common sense. For every 1000 men screened, at most, one will avoid a prostate cancer death at 10 years. But 30 to 40 will have erectile dysfunction, urinary incontinence, or both due to treatment, 2 men will experience a serious cardiovascular event, one will have a venous thromboembolic event, and one in 3000 screened will die from complications of surgical treatment.⁶

The USPSTF concluded that the benefits of PSA screening do not outweigh the harms, but acknowledged that shared decision making is still appropriate when a physician feels obliged to offer the test or a patient requests it.

What does shared decision making look like? Just offering screening and answering any questions is not good enough. We do an enormous disservice to our patients if we pretend that this is just a blood test and that we can decide later what to do with the information. Men will get biopsies and there will be complications. Cancer will be detected, and men will be treated, many unnecessarily.

Routine screening for prostate cancer in the absence of a truly formed decision is unacceptable.We need to tell our patients that the likelihood of avoiding a prostate cancer death over 10 years as a result of regular PSA screening is at most very small, and that many more men will suffer the harms of unnecessary treatment than will benefit. A few will die prematurely as a result of the complications of treating a screen-detected cancer.

If, with this knowledge, a patient places a higher value on the possibility of avoiding a prostate cancer death than he does on the known harms of diagnosis and treatment, he can still decide to be screened. He has made an informed decision. However, routine screening for prostate cancer in the absence of a truly informed decision is unacceptable.

Urinary incontinence (UI) affects almost half of all women in the United States.^1,2 Estimates suggest that the prevalence of UI gradually rises during young adult life, comes to a broad plateau in middle age, and then steadily increases from that plateau after age 65. Therefore, over the next 40 years, as the elderly population expands in size, the number of women affected by UI will significantly grow.³

For patients with UI, a multitude of therapeutic options are available. Which option is the best for your patient? In this article, we aim to answer that question by interpreting the results of four randomized trials, each of which directly compare two available treatment options. The first study examines patients with stress urinary incontinence (SUI), comparing the patients’ subjective improvement in urinary leakage and bladder function at 12 months after randomization to treatment with physiotherapy or midurethral sling surgery.

The three other trials examine patients with overactive bladder (OAB) and urgency urinary incontinence (UUI). Each trial directly compares the use of anticholinergic medications to an alternate treatment modality. Currently, anticholinergic medications and behavioral therapy are the recommended first-line therapies for OAB. Unfortunately, anticholinergic medications have poor patient compliance and significant systemic side effects.⁴ Caution should be used when considering anticholinergic medications in patients with impaired gastric emptying or a history of urinary retention. They also should be used with caution in elderly patients who are extremely frail. Additionally, clearance from an ophthalmologist must be obtained prior to starting anticholinergic medication in patients with narrow-angle glaucoma.⁵ Due to poor adherence and potential side effects, there is a growing effort to discover alternative treatment modalities that are safe and effective. Therefore, we chose to examine trials comparing: mirabegron versus tolterodine, percutaneous tibial nerve stimulation versus tolterodine, and onabotulinumtoxinA versus anticholingeric medications.

UI defined
Before discussing treatment options, we want to clarify the main types of UI (FIGURE). UI is defined as the complaint of involuntary loss of urine.  UI can be subdivided into SUI, OAB/UUI, or mixed urinary incontinence.⁶ While there are other less common genitourinary etiologies that can lead to UI, nongenitourinary etiologies are prevalent and can aggravate existing SUI or OAB (TABLE).

SUI is the complaint of involuntary loss of urine on effort or physical exertion (such as during sporting activities) or on sneezing or coughing. Often, SUI can be diagnosed by patient report alone and surgery can be considered in symptomatic patients who demonstrate cough leakage on physical examination and normal postvoid residual volumes.

UUI is the involuntary loss of urine associated with urgency; it often occurs in the setting of OAB, which is defined as the syndrome of urinary urgency, usually accompanied by frequency and nocturia, with or without UUI, in the absence of urinary tract infection or other obvious pathology (such as neurologic dysfunction, infection, or urologic neoplasm). OAB-dry is present when patients do not have leakage with urgency, but are bothered by urgency, frequency, and/or nocturia. OAB-wet occurs when a patient has urgencyincontinence.

The presence of both SUI and OAB/UUI is known as mixed urinary incontinence. Stress and urgency urinary symptoms often present together. In fact, 10% to 30% of women with stress symptoms are found to have bladder overactivity on subsequent evaluation.^2,7 Therefore, it is important to take a good history and consider urodynamic evaluation to confirm the diagnosis of SUI prior to surgery in women with mixed stress and urge symptoms, a history of a previous surgery for incontinence, or when there is a poor correlation of physical examination findings to reported symptoms.

Is surgery a first-line option for patients with SUI?

Labrie J, Berghmans BL, Fischer K, et al. Surgery versus physiotherapy for stress urinary incontinence. NEJM. 2013;369(12):1124−1133.

Physiotherapy, including pelvic floor muscle training (“Kegel exercises”), is utilized as a first-line treatment option for women with SUI that carries minimal risk for the patient. Midurethral sling surgery is often recommended if an initial trial of conservative treatment fails.⁷ Up to 50% of women treated with pelvic floor physiotherapy will ultimately undergo surgery to treat their SUI.⁸

Related article: Does urodynamic testing before surgery for stress incontinence improve outcomes? G. Willy Davila, MD (Examining the Evidence, December 2012)

Details of the study
This was a randomized, multicenter trial of women aged 35 to 80 years with moderate to severe SUI. After excluding women with previous incontinence surgery and stage 2 or higher pelvic organ prolapse, 460 participants were randomly assigned to undergo either a midurethral sling surgery or physiotherapy (pelvic floor muscle training). The primary outcome was subjective improvement in urinary leakage and bladder function at 12 months, as measured by the Patient Global Impression of Improvement (PGI-I), a 7-point Likert scale ranging from “very much worse” to “very much better.”

In an intention-to-treat analysis, subjective improvement at 12 months was significantly higher in women randomized to midurethral sling surgery than in women randomized to physiotherapy (91% vs 64%, respectively).

Ten percent of patients had adverse events (AEs); all were related to surgery. The most common AEs were hematoma, vaginal epithelial perforation, and bladder perforation.

Notably, women had the option to cross over to the other treatment modality if they desired. In the physiotherapy group, 49% of women elected to cross over to surgery, while 11% of those who underwent midurethral sling surgery elected to cross over to physiotherapy during the 12-month follow-up period. When analyzing results by treatment received, the investigators found that the proportion of women who reported improvement was significantly lower among women who underwent physiotherapy only (32%), versus sling only (94%), or sling after physiotherapy (91%).

This randomized trial was well-designed and included a variety of treatment centers (university and general hospitals) with interventions performed by experienced surgeons (all of whom had performed at least 20 sling surgeries) and physiotherapists educated specifically in pelvic floor physiotherapy. The study population was limited to patients with moderate to severe SUI as defined by the Sandvik severity index.⁹ Therefore, these results may not be applicable to patients with milder symptoms, for whom physiotherapy has been recommended as first-line therapy with consideration of surgery if physiotherapy fails to sufficiently improve symptoms.⁷

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Women with moderate to severe SUI without significant prolapse or a history of prior incontinence surgery have significantly better outcomes at 12 months after undergoing midurethral sling surgery versus physiotherapy. Physiotherapy carries little to no risk of adverse effects. Women with moderate to severe SUI should be counseled regarding the risks and benefits of both physiotherapy and midurethral sling surgery as initial treatment options.
Because stress and urgency urinary symptoms often present together, it is important to consider urodynamic evaluation to confirm SUI prior to surgery in women with:
• mixed stress and urge symptoms
• a history of a previous surgery for incontinence, or
• poor correlation of physical examination findings to reported symptoms.

Safety and tolerability of mirabegron versus tolterodine for OAB

Chapple CR, Kaplan SA, Mitcheson D, et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a beta(3)-adrenoceptor agonist, in overactive bladder. Eur Urol. 2013;63(2):296−305.

In the bladder, beta3-receptors located within the detrusor smooth muscle facilitate urine storage by relaxing the detrusor, enabling the bladder to fill.¹⁰ The activation of beta3-receptors is thought to increase the bladder’s ability to store urine, with the goal of decreasing urgency, frequency, nocturia, and urgency incontinence. An alternative to anticholinergic medications, mirabegron is a beta3-agonist approved by the US Food and Drug Administration (FDA) in 2012 for clinical use in the treatment of OAB.

Details of the study
Chapple and colleagues aimed to assess the 12-month efficacy and safety of mirabegron in a randomized, double-blind active controlled trial. The primary outcome was incidence and severity of treatment-emergent adverse effects (TEAEs); the secondary outcome was the change in OAB symptoms from baseline to up to 12 months. Patients experiencing OAB symptoms for more than 3 months were eligible and were subsequently enrolled if they averaged 8 or more voids per day and 3 or more episodes of urgency with or without incontinence on a 3-day bladder diary. A total of 2,444 patients were randomly assigned in a 1:1:1 fashion to mirabegron 50 mg daily, mirabegron 100 mg daily, or tolterodine extended release (ER) 4 mg daily.

There was a similar incidence (60% to 63%) of TEAEs across all three groups. The most common TEAEs were hypertension (defined as average systolic blood pressure [BP] >140 mm Hg or average diastolic BP >90 mm Hg at two consecutive visits), UTI, headache, nasopharyngitis, and constipation. The adjusted mean changes in BP from baseline to final visit were less than 1 mm Hg for both systolic and diastolic BP for patients taking both doses of mirabegron, as well as for patients taking tolterodine. The incidence of dry mouth was higher in the tolterodine group than the mirabegron groups. Mirabegron 50 mg daily and 100 mg daily improved incontinence symptoms within 1 month of starting therapy; the degree of improvement was similar to that seen in the patients taking tolterodine ER 4 mg daily.

Related article: New overactive bladder treatment approved by the FDA (August 2012)

Some caveats
This study was well-designed to assess the safety and tolerability of mirabegron versus tolterodine. The doses utilized in the study were at or above the FDA-approved dosage of 25 mg to 50 mg daily for OAB treatment. Although investigators found mirabegron to be a safe alternative to anticholinergic medication, the study was not designed or powered to examine the efficacy of mirabegron versus tolterodine. No formal comparison of efficacy was made between mirabegron or tolterodine, or between the 50-mg and 100-mg doses of mirabegron. Moreover, 81% of participants had been treated with mirabegron in earlier Phase 3 studies, so most were not treatment naïve, limiting the applicability of results.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Mirabegron should be considered as a potential treatment option for patients who demonstrate poor tolerance of or response to anticholinergic medications; however, caution should be used in patients with severe uncontrolled high BP, end-stage kidney disease, or severe liver impairment.

Consider percutaneous tibial nerve stimulation over tolterodine for OAB in select patients

Peters KM, Macdiarmid SA, Wooldridge LS, et al. Randomized trial of percutaneous tibial nerve stimulation versus extended-release tolterodine: Results from the overactive bladder innovative therapy trial. J Urol. 2009;182(3):1055−1061.

Neuromodulation utilizes electrical stimulation to improve bladder function and decrease OAB symptoms. First developed in the early 1980s by McGuire and colleagues, percutaneous tibial nerve stimulation (PTNS) was approved by the FDA in 2000 as Urgent PC and provides an outpatient, nonimplantable neuromodulation alternative to medication therapy for patients with OAB.^11,12 By directly stimulating the posterior tibial nerve, PTNS works via the S3 sacral nerve plexus to alter the micturition reflex and improve bladder function.

Details of the study
Patients were eligible for the study if they demonstrated 8 or more voids per day on a 3-day bladder diary (whether or not they had a history of previous anticholinergic drug use). A total of 100 ambulatory adults with OAB symptoms were enrolled and randomly assigned to PTNS 30-minutes per week or tolterodine ER 4 mg daily.

At 12 weeks, both groups demonstrated a significant improvement in OAB measures as well as validated symptom severity and quality-of-life questionnaire scores. Subjective assessment of improvement in OAB symptoms was significantly greater in the PTNS group than in the tolterodine group (79.5% vs 54.8%, respectively; P = .01). However, mean reduction of voids for 24 hours was not significantly different between the two groups.

Both treatments were well tolerated, with only 15% to 16% of patients in both groups reporting mild to moderate side effects. The tolterodine group did have a significantly higher risk of dry mouth; however, the risk of constipation was not significantly different between the groups.

Study limitations
The authors performed an important multicenter, nonblinded, randomized, controlled trial, which was one of the first trials to directly compare two OAB therapies. The generalizability of the findings were limited, as the cohort included mostly patients with dry OAB who had no objective measures on UUI episodes. In addition, this trial had a limited observation period of only 12 weeks. Information regarding the effect of treatment after cessation of weekly PTNS therapy was not examined. Therefore, we are not able to determine whether repeat sessions provide adequate maintenance in the long term.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
PTNS 30 minutes daily is as effective as tolterodine ER 4 mg daily for 12 weeks in reducing OAB symptoms. PTNS is a safe alternative that should be considered in patients with OAB who poorly tolerate or have contraindications to medication therapy.

OnabotulinumtoxinA is an effective therapy for OAB

Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy vs onabotulinumtoxinA for urgency urinary incontinence. NEJM. 2012;367(19):1803−1813.

The newest therapy for OAB is onabotulinumtoxinA, or Botox, which was FDA approved this year for the treatment of OAB in adults who cannot use or do not tolerate anticholinergic medications. Recommended doses are 100 U onabotulinumtoxinA in patients with idiopathic refractory OAB and 200 U onabotulinumtoxinA for patients with neurogenic OAB.

OnabotulinumtoxinA is a neurotoxin that blocks synaptic transmission at the neuromuscular junction to cause muscle paralysis and atrophy.¹³ Injecting onabotulinumtoxinA into the detrusor smooth muscle should relax the bladder and decrease sensations of urgency and frequency to achieve a longer duration of time for bladder filling and reduce the risk of urgency incontinence.

Effects of onabotulinumtoxinA appear to wear off over time, and patients may require repeat injections. Side effects of onabotulinumtoxinA therapy include an increased risk of UTI and the potential for urinary retention requiring intermittent self-catheterization.

Related article: Update on Pelvic Floor Dysfunction Autumn L. Edenfield, MD, and Cindy L. Amundsen, MD (October 2012)

Details of the study
The Anticholinergic Versus Botulinum Toxin Comparison (ABC) study was a multicenter, randomized, double-blind, double-placebo–controlled trial conducted in women without known neurologic disease with moderate to severe UUI (defined as >5 UUI episodes on a 3-day bladder diary). Women were randomly assigned to a single intradetrusor injection of 100 U onabotulinumtoxinA plus oral placebo or to a single intradetrusor injection of saline plus solifenacin 5 mg daily (with the option of dose escalation and then switching to trospium XR if no improvement was seen).

Of the 241 women included in the final analysis, approximately 70% in each group reported adequate control of symptoms at 6 months. Adequate control was defined as a response of “agree strongly” or “agree” to the statement: “This treatment has given me adequate control of my urinary leakage.” Women in the onabotulinumtoxinA group were significantly more likely than women in the anticholinergic medication group to report complete resolution of UUI at 6 months (27% vs 13%, P = .003). However, the mean reduction in episodes of UUI per day and the improvements in quality-of-life questionnaire scores were found to be similar. Interestingly, worse baseline UUI was associated with greater reduction in episodes of UUI for both therapies.

This was a rigorous and well-executed double-blind, double-placebo−controlled randomized trial. By utilizing broad inclusion criteria and enrolling patients both with and without previous exposure to anticholinergic medications, the generalizability of study findings are greatly improved. Because this study did not examine the effect or efficacy of repeat injections, these findings have limited applicability to patients undergoing multiple onabotulinumtoxinA injections.

When considering use in your patient population, keep the possible side effects in mind.There were important differences in the side effects experienced with each therapy. Specifically, while the anticholinergic group had a higher frequency of dry mouth (46% anticholinergic vs 31% onabotulinumtoxinA, P = .02), the onabotulinumtoxinA group demonstrated higher rates of incomplete bladder emptying requiring catheterization (peak of 5% at 2 months) and greater risk of UTI (33% onabotulinumtoxinA vs 13% anticholinergic, P <.001).

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This study showed that, among women with UUI, anticholinergic medication and onabotulinumtoxinA are equally effective in reducing UUI episodes and improving quality of life. It is important to consider the side effect profile, determine the patient’s preferences, and weigh the risks and benefits of each therapy when deciding what is the best treatment for your individual patient.

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