Physician's Weekly Updates: Diabetes 2015 by Physician's Weekly

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DIABETES

Health & Diabetes

Predicting

Drug Adherence

CVD Risk &

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December 2015

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of Medicare Part D patients1 And preferred coverage for more than 80% of commercial patients1 Learn more and register for updates at INVOKANAhcp.com *Data on file. Based on TRx data sourced from IMS NPA Database, weekly data through 11/09/15. Reference: 1. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ.

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December 2015

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Table of Contents Diabetes Drug Adherence: Assessing Key Determinants – M. Sue Kirkman, MD 4

Strategies for Improving Diabetes Care

A Message From the Editor At Physician’s Weekly, we are proud to present this monograph featuring several features that are applicable to those managing patients with diabetes. Created with the assistance of key opinion leaders and experts from the American Diabetes Association, these articles discuss important aspects of diabetes care and strategies to improve current practices. In the upcoming months, Physician’s Weekly will continue to feature topics on diabetes and its complications. Your feedback and opinions are welcome; email keith.doria@physweekly.com. Thanks for reading! Sincerely,

– Alka Kanaya, MD 8 Keith D’Oria

Editorial Director, Physician’s Weekly

CVD Risk & Diabetes: A Focus on Lipids – Rodica Pop-Busui, MD, PhD

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Physician’s Weekly™ (ISSN 1047-3793) is published by Physician’s Weekly, LLC, a division of M/C Holding Corp. The service is free for qualifying institutions. Please contact us at editor@physweekly.com for more information. Offices: Physician’s Weekly, LLC, 180 Mount Airy Road, Suite 102, Basking Ridge, NJ 07920; and 2127 2nd Avenue North, Fort Dodge, IA 50501. Reproduction without written permission from the publisher is prohibited. Copyright 2015, Physician’s Weekly, LLC. Publication of an advertisement or other product mention in Physician’s Weekly should not be construed as an endorsement of the product or the manufacturer’s claims. The appearance of or reference to any person or entity in this publication (including images) does not constitute an expressed or implied endorsement of the product mentioned. The reader is advised to consult appropriate medical literature and the product information currently provided by the manufacturer of each drug to verify indications, dosage, method, duration of administration, and contraindications. All editorial is developed independent of influence from advertising brands/companies.

Diabetes Drug Adhe

Assessing Key Determ

Several modifiable and non-modifiable factors appear to be associated with adherence to anti-diabetic medications. Providers and healthcare system leaders should collaborate to develop strategies to reduce outof-pocket costs in order to improve adherence.

ultiple medications are often prescribed to help adults with type 2 diabetes manage hyperglycemia, diabetes-associated conditions like hypertension M. Sue Kirkman, MD and dyslipidemia, and other comorbidities. â&#x20AC;&#x153;Prior studies have shown 4

that non-adherence to diabetes medications is associated with many adverse outcomes,â&#x20AC;? says M. Sue Kirkman, MD. Research indicates that better adherence to diabetes medications improves control of intermediate risk factors. It also reduces the likelihood of being hospitalized, can lower healthcare costs, and may decease mortality.

erence:

minants

Taking a Closer Look Studies aiming to estimate rates of adherence to diabetes medications vary widely depending on the types of patients involved in the analysis and how investigators define adherence. Most analyses tend to look at either individual-level or system-level factors independently, but few have used large generalizable cohorts. To address this research gap, Dr. Kirkman and colleagues had a study published in Diabetes Care that used a large national database to look at adherence to oral diabetes medications in more than 200,000 adults with type 2 diabetes in the United States. For the investigation, the study team used the medication possession ratio, which Dr. Kirkman notes is a fairly standard way to assess adherence.

This Physician’s Weekly feature on assessing key determinants in diabetes drug adherence was completed in cooperation with the experts at the American Diabetes Association.

“We pre-specified a number of variables related to patient, provider, and prescription factors, and then looked at their association with adherence,” she says. “A multivariate model was then developed to look at the independent effects of each variable since many of them correlate with one another.”

Important Findings Overall, about 70% of patients involved in the study were adherent to their medications. “We identified several factors that were associated with non-adherence, including younger age, being new to diabetes therapy, being female, and being on few other medications,” explains Dr. Kirkman (Table 1). Specifically with regard to visit www.physiciansweekly.com 5

Table 1

Patient Factors

The table below depicts odds ratios for a multivariate model of patient factors associated with diabetes medication adherence: Patient Factor

Odds Ratio

Patient exposure to diabetes therapy New to therapy vs continuing therapy

0.39

Patient age-group 25 to 44 years vs 45 to 64 years

0.51

65 to 74 years vs 45 to 64 years

1.27

>75 years vs 46 to 64 years

1.41

Patient sex Male vs female

1.14

Patient education Vocational vs high school equivalent

1.06

College grad vs high school equivalent

1.20

Graduate school vs high school equivalent

1.41

Patient income $30k to $60k vs <$30k

0.93

>$60k vs <$30k

1.27

Patient geographic region Midwest vs West

1.12

Northeast vs West

1.04

South vs West

1.00

Source: Adapted from: Kirkman MS, et al. Diabetes Care. 2015;38:604-609.

age, patients aged 25 to 44 were 49% less likely to be adherent when compared with patients aged 45 to 64. Patients between the ages of 65 and 74 were 27% more likely to be adherent, and those aged 75 and older were 41% more likely to be adherent when compared with the 45-to-64 age group. The study team also found that patients who were new to therapy 6

were 61% less likely to adhere to their diabetes medications. With regard to demographics, men were significantly more likely to adhere to their diabetes drugs than women. Education was also associated with adherence, with patients being more likely to adhere to their medications if they had a higher estimated academic achievement. Patients who completed graduate school were 41% more likely to be adherent than those with a high school equivalent education. Patients with an annual income that topped $60,000 were also more likely to be adherent when compared with those making less than $30,000. Little variation was seen across geographic regions, but patients living in the Midwest were 12% more likely to be adherent than those in the West.

Other Key Factors â&#x20AC;&#x153;Non-adherence was also associated with higher out-of-pocket costs and use of retail pharmacies versus mail order pharmacies,â&#x20AC;? says Dr. Kirkman. Patients using mail order pharmacies were more than twice as likely to be adherent to their medications when compared with those who filled their prescriptions at retail pharmacies (Table 2). Total daily pill burden was also an adherence factor. For each additional pill that patients took per day, adherence to antidiabetic drugs increased by 22%. The authors also found that diabetes medication adherence decreased by 11% for each additional $15 that was spent in out-of-pocket costs per month. Several prescriber factors were also examined in the analysis. No significant differences were seen in patient adherence by sex of the prescriber, and the effect size of prescriber age was very small. In addition, no significant differences

Clinicians need to be aware of these factors and target programs or interventions to improve adherence.” —M. Sue Kirkman, MD in adherence were observed between primary care and endocrinologist prescribers. However, patients with non-endocrinologist specialists who were their prescribers had slightly but significantly lower adherence than those with primary care prescribers.

Examining the Implications “More research is needed to gain a better understanding about why being new to diabetes therapy or being on fewer medications overall was associated with lower adherence in our study,” Dr. Kirkman says. “We can only speculate on the potential rationale behind this, but it’s possible that these patients may not view themselves as truly being ‘ill’ and may be less likely to take medications, especially when the disease is asymptomatic. Regarding patient age as a factor, it’s possible that older patients have more comorbidities and are used to taking medications regularly. Their daily routine might make them more likely to adhere to their diabetes medications.” Dr. Kirkman says findings of the study are helpful to healthcare providers in raising awareness of

both modifiable and non-modifiable factors that are associated with lower adherence. “Clinicians need to be aware of these factors and target programs or interventions to improve adherence,” she says. “Healthcare providers and system leaders should work together to target potentially modifiable factors, such as getting more patients to use mail order pharmacies and doing more to lower patients’ out of pocket costs.”

Prescription & Prescriber Factors Table 2

The table below depicts odds ratios for a multivariate model of prescription and prescriber factors associated with diabetes medication adherence: Prescription Factors

Odds Ratio

Prescription drug channel: mail vs retail

2.09

Total pill burden

1.22

Out-of-pocket costs (30 days)

0.89

Prescriber Factors

Odds Ratio

Specialty: endocrinologist vs primary care

1.01

Specialty: other specialist vs primary care

0.91

Prescriber age

1.002

Source: Adapted from: Kirkman MS, et al. Diabetes Care. 2015;38:604-609.

M. Sue Kirkman, MD, has indicated to Physician’s Weekly that she receives research support from Novo Nordisk. Readings & Resources Kirkman MS, Rowan-Martin MT, Levin R, et al. Determinants of adherence to diabetes medications: findings from a large pharmacy claims database. Diabetes Care. 2015;38:604-609. Available at: http://care.diabetesjournals.org/content/38/4/604.abstract. | American Diabetes Association. Standards of Medical Care in Diabetes—2015. Diabetes Care. 2014;38:S1-S93. Available at: http:// professional.diabetes.org/admin/UserFiles/0%20-%20Sean/Documents/January%20Supplement%20Combined_Final.pdf. | Asche C, LaFleur J, Conner C. A review of diabetes treatment adherence and the association with clinical and economic outcomes. Clin Ther. 2011;33:74-109. | Bogner HR, de Vries HF, O’Donnell AJ, Morales KH. Measuring concurrent oral hypoglycemic and antidepressant adherence and clinical outcomes. Am J Manag Care. 2013;19:e85-e92. | Juarez DT, Tan C, Davis J, Mau M. Factors affecting sustained medication adherence and its impact on health care utilization in patients with diabetes. J Pharm Health Serv Res. 2013;4:89-94.

visit www.physiciansweekly.com 7

STRATEGIES for Improving Diabetes Care

With the epidemic continuing to burden healthcare systems throughout the country, efforts are needed to encourage clinicians to use patient-centered strategies and evidence-based treatments when managing type 2 diabetes. Proactive engagement and linking patients to supportive care are paramount.

ccording to the most recent estimates, more than 29 million Americans—or slightly more than 9% of the population—has diabetes. Nearly 2 million new cases Alka Kanaya, MD of diabetes are diagnosed each year, highlighting the need for greater prevention efforts. When managing patients with diabetes and those at risk for the disease, the American Diabetes Association recommends that clinicians strive to provide patient-centered care, consider diabetes across the life span, and serve as advocates for patients with diabetes. 8

“A key management strategy for patients with diabetes is to recognize that one size does not fit all,” says Alka Kanaya, MD. “When following evidence-based guidelines for managing the disease, it’s important to adapt care based on each individual patient’s specific characteristics.” Because patients with diabetes are also at higher risk of heart disease, a patientcentered approach should be used. This includes a comprehensive plan to reduce cardiovascular risk by addressing blood pressure (BP) and lipid control, smoking cessation, weight management, and healthy lifestyle changes that include adequate physical activity.

This Physician’s Weekly feature on strategies for improving diabetes care was completed in cooperation with the experts at the American Diabetes Association.

Care Delivery Systems In addition to taking a patient-centered approach, improving coordination between clinical teams is critical as patients pass through different stages of life. “Ongoing efforts are needed to prevent the complications that can occur in patients with type 2 diabetes,” Dr. Kanaya says. “Studies suggest that there has been steady improvement in the proportion of patients achieving recommended levels of A1C, BP, and cholesterol in the last 10 years, but many patients still do not meet their personal targets. Variations in quality of diabetes care have persisted, indicating that there is potential to improve care delivery systems.”

A major barrier to optimizing care is a delivery system that is often fragmented, highlighting the need to use collaborative approaches to managing patients. The Chronic Care Model (CCM) has been shown to be an effective framework for improving the quality of diabetes care and is recommended by the American Diabetes Association (Table 1). The CCM model advocates moving from a reactive to a proactive care delivery system in which planned visits are coordinated through a team-based approach. The CCM also involves self-management support, decision support, and community resources, among other features. “It’s important to clearly define the roles of clinical staff and promote self-management practices,” adds Dr. Kanaya. visit www.physiciansweekly.com 9

We should harness technology using text messa electronic health record as tools to help patient care of their clinicians.” Key Objectives The National Diabetes Education Program (NDEP) maintains an online resource to help clinicians design and implement more effective healthcare delivery systems for those with diabetes. The NDEP outlines three specific objectives for clinicians: 1) optimize provider and team behaviors, 2) support behavioral change for patients, and 3) change the care system (Table 2). To optimize provider and team behavior, the care team should prioritize timely and appropriate intensification of lifestyle and/or

Summarizing Recommendations Table 1

Below is a summary of recommendations from the American Diabetes Association on strategies for improving care: Recommendation

Level of Evidence

A patient-centered communication style that incorporates patient preferences, assesses literacy and numeracy, and addresses cultural barriers to care should be used.

Treatment decisions should be timely and founded on evidence-based guidelines that are tailored to individual patient preferences, prognoses, and comorbidities.

Care should be aligned with components of the Chronic Care Model to ensure productive interactions between a prepared, proactive practice team and an informed, activated patient.

When feasible, care systems should support team-based care, community involvement, patient registries, and decision support tools to meet patient needs.

Source: Adapted from: American Diabetes Association, et al. Diabetes Care. 2015;38:S5-S7.

pharmaceutical therapy for patients who have not achieved targeted A1C, BP, and cholesterol levels. Goals should be set explicitly with patients, and language or cultural barriers to care should be identified and addressed. A systematic approach should also be set to support and educate patients with regard to behavioral changes. “We should harness technology using text messages, applications, and the electronic health record as tools to help patients when they’re outside the care of their clinicians,” says Dr. Kanaya. “Technology can help with various aspects of diabetes care, including healthy lifestyle changes, self-management, and prevention of complications.” Attention should also be paid to the emotional concerns that patients with diabetes may experience. To improve quality of diabetes care, the American Diabetes Association recommends that institutions redesign the care process to actively advocate for patients. “Patients should be educated about their disease, and efforts should be made to remove potential financial barriers,” Dr. Kanaya says. “Reducing out-ofpocket costs for education, self-monitoring of diabetes-related complications, and medications is important. As a whole, we’re behind the curve with regard to optimizing diabetes management. We need to take a more organized, systematic approach and involve a coordinated team of dedicated professionals in which patientcentered, high-quality care is the top priority.”

ges, applications, and the s when they’re outside the —Alka Kanaya, MD

Meeting Treatment Goals Despite the best efforts of healthcare providers, some patients may still not achieve desired treatment goals. When such cases occur, Dr. Kanaya says it is important to reassess treatment regimens to identify any potential barriers to reaching therapeutic goals. Potential barriers include income, health literacy, diabetes-related distress, depression, and other competing demands. It is also important to consider patients’ culture and tailor management strategies. In some cases, referral to a medical social worker for assistance with insurance coverage and behavior assessments may be helpful. “Ultimately, we need to take a holistic approach and make every effort to prevent diabetes complications before they emerge,” says Dr. Kanaya. Alka Kanaya, MD, has indicated to Physician’s Weekly that she has or has had no financial interests to report.

More Effective Healthcare for Diabetes: Key Objectives Table 2

The National Diabetes Education Program (NDEP) maintains an online resource (www.betterdiabetescare.nih.gov) to help healthcare professionals design and implement more effective healthcare delivery systems for those with diabetes. NDEP has identified three specific objectives:

Objective 1: Optimize Provider & Team Behavior Prioritize timely and appropriate intensification of lifestyle and/or pharmaceutical therapy for patients who have not achieved beneficial levels of blood pressure, lipid, or glucose control. Utilize these strategies: • Use explicit goal setting • Integrate evidencebased guidelines and with patients. clinical information • Identify and address tools into the process language, numeracy, or of care. cultural barriers to care.

• Incorporate care management teams, including nurses, pharmacists, and other providers.

Objective 2: Support Patient Behavior Change Successful diabetes care requires a systematic approach to supporting patients’ behavior change efforts, including: • Healthy lifestyle changes.

• Disease selfmanagement.

• Prevention of diabetes complications.

High-quality diabetes self-management education (DSME) and ongoing diabetes self-management support improves patient self-management, satisfaction, and glucose control. National DSME standards call for an integrated approach that includes: • Clinical content and skills.

• Behavioral strategies (goal setting, problem solving).

• Engagement with emotional concerns in each needed curriculum content area.

Objective 3: Change the Care System To increase quality of diabetes care: • Base care on evidence- • Implement electronic based guidelines. health record tools.

• Activate and educate patients.

• Expand the role of teams and staff.

• Reduce patient outof-pocket costs for diabetes education, eye exams, self-monitoring of blood glucose, and necessary medications.

• Implement more intensive disease management strategies. • Redesign the care process. Readings & Resources American Diabetes Association. Strategies for Improving Care. Diabetes Care. 2015;38:S5-S7. Available at: http://care.diabetesjournals.org/content/38/ Supplement_1/S5.full. | American Diabetes Association. Standards of Medical Care in Diabetes—2015. Diabetes Care. 2014;38:S1-S93. Available at: http:// professional.diabetes.org/admin/UserFiles/0%20-%20Sean/Documents/ January%20Supplement%20Combined_Final.pdf. | Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999-2010. N Engl J Med. 2013;368:1613-1624. | Stellefson M, Dipnarine K, Stopka C. The chronic care model and diabetes management in US primary care settings: a systematic review. Prev Chronic Dis. 2013;10:E26.

• Identify, develop, and engage community resources and public policy that support healthy lifestyles. • Remove financial barriers.

Consider initiatives, such as the Patient-Centered Medical Home, for improving outcomes through coordinated primary care. Offer new opportunities for team-based chronic disease care. Additional strategies to improve diabetes care include: • Develop reimbursement structures • U se incentives that accommodate that reward the provision of personalized care goals. appropriate and high-quality care. Source: Adapted from: American Diabetes Association, et al. Diabetes Care. 2015;38:S5-S7.

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CVD Risk & Diabetes:

A Focus on Dyslipidemia is a common condition that coexists with type 2 diabetes and has been identified as a clear risk factor for cardiovascular disease (CVD). Controlling individual cholesterol levels is critically important to preventing or slowing CVD in people with diabetes.

ardiovascular disease (CVD) has been identified as a major cause of morbidity and mortality for patients living with diabetes. In addition to hypertension, Rodica Popobesity, and smoking, dysBusui, MD, PhD lipidemia has been well documented to be a common condition that coexists among people with type 2 diabetes and 12

is an important risk factor for CVD. â&#x20AC;&#x153;Effective control of all cardiovascular risk factors has been shown to help prevent or slow the progression of CVD in people with diabetes,â&#x20AC;? says Rodica Pop-Busui, MD, PhD. Each year, the American Diabetes Association updates its Standards of Care document to provide the best possible guidance to healthcare providers for the management of the complex diabetic patients. A section of the 2015

This Physicianâ&#x20AC;&#x2122;s Weekly feature on CVD risk management in diabetes that focuses on lipids was completed in cooperation with the experts at the American Diabetes Association.

Lipids document has been dedicated to managing CVD and associated risk factors, including dyslipidemia, with lifestyle interventions and medications. This section offers information on lipid screening and treatment goals (Table 1). A key emphasis of these recommendations is placed on lifestyle interventions, including medical nutrition therapy, increasing physical activity, losing weight, and quitting smoking. These interventions, if adhered to, have been shown to effectively reduce risk factors for CVD as a result of lowering LDL cholesterol, blood pressure, and weight.

Starting Statins According to the American Diabetes Association, patients with type 2 diabetes have a higher risk of lipid abnormalities and, as such, should be

considered for statin therapy. â&#x20AC;&#x153;Multiple clinical trials have shown that using statins as primary and secondary prevention can have an important effect on patient outcomes and CVD risk reduction,â&#x20AC;? explains Dr. Pop-Busui. Reductions in CVD risk tend to be greatest among people at highest risk and those with very high LDL cholesterol levels, but the overall benefits of statins in people with diabetes at moderate or high risk for CVD are also convincing, making statins the drugs of choice for LDL cholesterol lowering and cardioprotection. The 2015 Standards of Care document revised recommendations on when to initiate and intensify statin therapy based on risk profiles using age and the number of additional CVD risk factors that are present, rather than on LDL cholesterol levels (Table 2, see page 23). All patients with visit www.physiciansweekly.com 13

Lipid Screening & Treatment Goals Table 1

Recommendation

Level of Evidence

In adults, a screening lipid profile is reasonable at the time of first diagnosis, at the initial medical evaluation, and/or at age 40 and periodically thereafter (eg, every 1-2 years).

Lifestyle modification focusing on the reduction of saturated fat, trans fat, and cholesterol intake; increase of omega-3 fatty acids, viscous fiber, and plant stanols/sterols; weight loss (if indicated); and increased physical activity should be recommended to improve the lipid profile in patients with diabetes.

Ongoing Therapy & Monitoring

Intensify lifestyle therapy and optimize glycemic control for patients with elevated triglyceride levels (≥150 mg/dL) and/or low HDL cholesterol (<40 mg/dL for men, <50 mg/dL for women). For patients with fasting triglyceride levels ≥500 mg/ dL, evaluate for secondary causes and consider medical therapy to reduce risk of pancreatitis.

For patients of all ages with diabetes and overt cardiovascular disease (CVD), high-intensity statin therapy should be added to lifestyle therapy.

For patients with diabetes younger than 40 with additional CVD risk factors, consider using moderateor high-intensity statin and lifestyle therapy.

For patients with diabetes aged 40-75 without additional CVD risk factors, consider using moderate-intensity statin and lifestyle therapy.

For patients with diabetes aged 40-75 with additional CVD risk factors, consider using high-intensity statin and lifestyle therapy.

For patients with diabetes older than 75 without additional CVD risk factors, consider using moderateintensity statin therapy and lifestyle therapy.

For patients with diabetes older than 75 with additional CVD risk factors, consider using moderate- or high-intensity statin therapy and lifestyle therapy.

In clinical practice, providers may need to adjust intensity of statin therapy based on individual patient response to medication (eg, side effects, tolerability, LDL cholesterol levels).

Cholesterol laboratory testing may be helpful in monitoring adherence to therapy, but may not be needed once the patient is stable on therapy.

Combination therapy (statin/fibrate and statin/ niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not generally recommended.

Statin therapy is contraindicated in pregnancy.

In adults with diabetes, a screening lipid profile consisting of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides should be performed when patients are first diagnosed as well as at their initial medical evaluation. This screening should also be performed beginning at age 40 or sooner if indicated. “Once patients are started on a statin, it’s important to monitor adherence and efficacy,” adds Dr. Pop-Busui. If patients are adhering to statins but without an LDL cholesterol level response, clinical judgement should be used to determine the need for and timing of lipid panels. The American Diabetes Association recommends that hypertriglyceridemia be addressed with dietary and lifestyle changes. In cases of severe hypertriglyceridemia, immediate pharmacologic therapy may be warranted to reduce the risk of acute pancreatitis. Low levels of HDL cholesterol are often associated with elevated triglyceride levels and are a prevalent pattern of dyslipidemia in persons with type 2 diabetes. However, the evidence base for drugs that target these lipids is significantly less robust than that for statin therapy. Continued on page 23

Source: Adapted from: American Diabetes Association. Diabetes Care. 2015;38:S49-S57.

diabetes aged 40 and older should be considered for moderate-intensity statin treatment, if clinically indicated, in addition to lifestyle therapy. For adults with diabetes who are older than 75, the data regarding statins are more limited. “These patients should be provided statins based on their individualized risk profile,” Dr. PopBusui says. “The risk-benefit profile should be routinely evaluated for these patients, and titration should be performed as needed.”

MO 6 PR M RE T ES IL HA TO CRI LIO N DA PTI N

TE 1 ON * S

In the treatment of type 2 diabetes, help

INSPIRE PATIENTS TO

FERRED PRE

GO FURTHER

COVERAGE FOR

>80% OF COMMERCIAL & MEDICARE PART D PATIENTS1

*Data on file. Based on TRx data sourced from IMS NPA Database, weekly data through 11/9/15.

INVOKANA速 is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. INVOKANA速 is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS >> History of a serious hypersensitivity reaction to INVOKANA速 >> Severe renal impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

visit www.physiciansweekly.com 15

#1 ≈1% A1C From a baseline

BODY WEIGHT†

of ≈8%

BLOOD PRESSURE†

PRESCRIBED1

PROVEN

SAFETY PROFILE

SGLT2 INHIBITOR At 300-mg dose2

vs Januvia®2,3

>80

Preferred commercial & Medicare Part D coverage1

Learn more and register for updates at

INVOKANAhcp.com

SGLT2=sodium-glucose co-transporter 2.

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS and PRECAUTIONS >> Hypotension: INVOKANA® causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA®, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system, or patients with low systolic blood pressure. Before initiating in patients with ≥1 of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating. >> Impairment in Renal Function: INVOKANA® increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiation. More frequent renal function monitoring is recommended in patients with an eGFR <60 mL/min/1.73 m2. >> Hyperkalemia: INVOKANA® can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. >> Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: INVOKANA® can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA®.

Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

INVOKANA® 300 mg: GREATER REDUCTIONS in A1C vs Januvia® 100 mg, from a baseline of ≈8% at 52 weeks in patients inadequately controlled on metformin + a sulfonylurea2 Adjusted Mean Change in A1C From Baseline (%) Mean baseline:

8.13%

8.12%

–0.66 –1.03 Januvia® (sitagliptin) 100 mg + metformin and a sulfonylurea (n=378)

INVOKANA® 300 mg + metformin and a sulfonylurea (n=377)

>> INVOKANA® 300 mg difference from Januvia® 100 mg: –0.37% (95% CI: –0.50, –0.25; P<0.05) BLEED:11.5”

TRIM:10.5”

SAFETY:9.5”

Secondary endpoints: Greater reductions in body weight and systolic blood pressure (SBP) vs Januvia® 100 mg2,3

GREATER REDUCTIONS in body weight2*

GREATER REDUCTIONS in SBP3*

>> Januvia® 100 mg change from baseline: +0.3% >> INVOKANA® 300 mg change from baseline: –2.5% >> INVOKANA® 300 mg difference from Januvia® 100 mg: –2.8%; P<0.001

>> Januvia® 100 mg change from baseline: +0.9 mm Hg >> INVOKANA® 300 mg change from baseline: –5.1 mm Hg >> INVOKANA® 300 mg difference from Januvia® 100 mg: –5.9 mm Hg; P<0.001

Incidence of hypoglycemia2

Similar overall incidence of AEs vs Januvia®3

Januvia® 100 mg: 40.7%; INVOKANA® 300 mg: 43.2% The incidence of hypoglycemia increases when used in combination with insulin or an insulin secretagogue. INVOKANA® is not indicated for weight loss or as an antihypertensive treatment.

Incidences of AEs were similar between groups, except for: Male/female genital mycotic infection, Januvia® 100 mg: 0.5%/4.3%; INVOKANA® 300 mg: 9.2%/15.3% Increased urine frequency/volume, Januvia® 100 mg: 1.3%/0%; INVOKANA® 300 mg: 1.6%/0.8%

*Adjusted mean change from baseline. Indicated trademarks are registered trademarks of their respective owners.

A randomized, double-blind, active-controlled, 52-week study of 755 patients with type 2 diabetes inadequately controlled on maximally or near-maximally effective doses of metformin (≥2000 mg/day, or ≥1500 mg/day if higher dose not tolerated) and a sulfonylurea. The primary endpoint was the change in A1C from baseline to 52 weeks. 2,3 INVOKANA® starting dose: 100 mg once daily. In patients tolerating the starting dose who have an eGFR ≥60 mL/min/1.73 m2 and require additional glycemic control, the dose can be increased to 300 mg once daily.2

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IMPORTANT SAFETY INFORMATION (cont’d)

>> Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA®; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKANA®, treat per standard of care, and monitor until signs and symptoms resolve. >> Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA®. Consider factors that contribute to fracture risk prior to initiating INVOKANA®. >> Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with INVOKANA®. Monitor LDL-C and treat per standard of care after initiating. >> Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA® or any other antidiabetic drug. DRUG INTERACTIONS >> UGT Enzyme Inducers: Rifampin: Co-administration of INVOKANA® with rifampin decreased INVOKANA® area under the curve (AUC) by 51% and therefore may decrease efficacy. If an inducer of UGT enzymes must be co-administered with INVOKANA®, consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA® 100 mg once daily, have an eGFR ≥60 mL/ min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR <60 mL/ min/1.73 m2 who require additional glycemic control. >> Digoxin: There was an increase in the AUC and mean peak drug concentration of digoxin (20% and 36%, respectively) when co-administered with INVOKANA® 300 mg. Monitor appropriately. >> Positive Urine Glucose Test: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose test results. Use alternative methods to monitor glycemic control. >> Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

had a higher incidence of adverse reactions related to reduced intravascular volume (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years (‒0.61% with INVOKANA® 100 mg and ‒0.74% with INVOKANA® 300 mg) compared to younger patients (‒0.72% with INVOKANA® 100 mg and ‒0.87% with INVOKANA® 300 mg). >> Renal Impairment: Efficacy and safety were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy and a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with 300 mg were more likely to experience increases in potassium. INVOKANA® is not recommended in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease, or receiving dialysis. >> Hepatic Impairment: INVOKANA® has not been studied in patients with severe hepatic impairment and is not recommended in this population. OVERDOSAGE >> In the event of an overdose, contact the Poison Control Center and employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as needed. ADVERSE REACTIONS >> The most common adverse reactions associated with INVOKANA® (5% or greater incidence) were female genital mycotic infections, urinary tract infections, and increased urination. Please see brief summary of full Prescribing Information at right and on the following pages. References: 1. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ. 2. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2015. 3. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial [published correction appears in Diabetes Care. 2013;36(12):4172]. Diabetes Care. 2013;36(9):2508-2515.

USE IN SPECIFIC POPULATIONS >> Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA® in pregnant women. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. >> Nursing Mothers: It is not known if INVOKANA® is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, discontinue INVOKANA®. >> Pediatric Use: Safety and effectiveness in patients <18 years of age have not been established. >> Geriatric Use: 2034 patients ≥65 years and 345 patients ≥75 years were exposed to INVOKANA® in 9 clinical studies. Patients ≥65 years

Janssen Pharmaceuticals, Inc.

Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2015

December 2015

037307-151023

038374-150810

>> Genital Mycotic Infections: INVOKANA® increases risk of genital mycotic infections. Patients with history of these infections and uncircumcised males were more likely to develop these infections. Monitor and treat appropriately.

INVOKANA®

(canagliflozin) tablets, for oral use Brief Summary of Prescribing Information.

BLEED:11.5”

TRIM:10.5”

SAFETY:9.5”

INDICATIONS AND USAGE INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) in full Prescribing Information]. Limitation of Use: INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. CONTRAINDICATIONS • History of a serious hypersensitivity reaction to INVOKANA [see Warnings and Precautions]. • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease (ESRD), or patients on dialysis [see Warnings and Precautions and Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensinaldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Impairment in Renal Function: INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are at an increased risk of developing hyperkalemia [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. Genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately. Hypersensitivity Reactions: Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions]. Bone Fracture: An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA. Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Adverse Reactions]. Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions]. Monitor LDL-C and treat if appropriate after initiating INVOKANA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug. ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: • Hypotension [see Warnings and Precautions] • Impairment in Renal Function [see Warnings and Precautions] • Hyperkalemia [see Warnings and Precautions] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions] • Genital Mycotic Infections [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Bone Fracture [see Warnings and Precautions] • Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions]

INVOKANA® (canagliflozin) tablets Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pool of Placebo-Controlled Trials: The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) in full Prescribing Information]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. Table 1: Adverse Reactions From Pool of Four 26−Week Placebo-Controlled Studies Reported in ≥ 2% of INVOKANA-Treated Patients* INVOKANA INVOKANA Placebo 100 mg 300 mg Adverse Reaction N=646 N=833 N=834 Female genital mycotic 3.2% 10.4% 11.4% infections† Urinary tract infections‡ 4.0% 5.9% 4.3% 0.8% 5.3% 4.6% Increased urination§ Male genital mycotic 0.6% 4.2% 3.7% infections¶ Vulvovaginal pruritus 0.0% 1.6% 3.0% 0.2% 2.8% 2.3% Thirst# Constipation 0.9% 1.8% 2.3% Nausea 1.5% 2.2% 2.3% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430). ‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404). # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions for canagliflozin was evaluated in a larger pool of patients participating in placebo- and active-controlled trials. The data combined eight clinical trials [see Clinical Studies (14) in full Prescribing Information] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2).

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INVOKANA® (canagliflozin) tablets

The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg, and 1.1% with INVOKANA 300 mg). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 2) [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Use in Specific Populations].

Table 3: Changes in Serum Creatinine and eGFR Associated with INVOKANA in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial (continued)

Table 2: Proportion of Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials) Comparator INVOKANA INVOKANA Group* 100 mg 300 mg Baseline Characteristic % % % Overall population 1.5% 2.3% 3.4% 75 years of age and older† 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1% Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1 of the listed risk factors Falls: In a pool of nine clinical trials with mean duration of exposure to INVOKANA of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The higher risk of falls for patients treated with INVOKANA was observed within the first few weeks of treatment. Impairment in Renal Function: INVOKANA is associated with a dosedependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes. Table 3: Changes in Serum Creatinine and eGFR Associated with INVOKANA in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial Placebo N=646 Creatinine (mg/dL) 0.84 87.0 eGFR (mL/min/1.73 m2) Creatinine (mg/dL) 0.01 -1.6 eGFR (mL/min/1.73 m2)

Baseline Pool of Four Week 6 Placebo- Change Controlled End of Creatinine (mg/dL) Trials Treatment Change* eGFR (mL/min/1.73 m2)

INVOKANA INVOKANA 100 mg 300 mg N=833 N=834 0.82 0.82 88.3 88.8 0.03 0.05 -3.8 -5.0

0.01

0.02

0.03

-1.6

-2.3

-3.4

Placebo N=90 Creatinine (mg/dL) 1.61 Baseline 40.1 eGFR (mL/min/1.73 m2) Moderate Creatinine (mg/dL) 0.03 Week 3 Renal -0.7 eGFR (mL/min/1.73 m2) Impairment Change Trial End of Creatinine (mg/dL) 0.07 Treatment -1.5 Change* eGFR (mL/min/1.73 m2)

INVOKANA INVOKANA 100 mg 300 mg N=90 N=89 1.62 1.63 39.7 38.5 0.18 0.28 -4.6 -6.2 0.16

0.18

-3.6

-4.0

* Week 26 in mITT LOCF population In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline. In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 2.2% with INVOKANA 300 mg had a significant renal function decline. In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed. Use of INVOKANA has been associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment. In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions]. Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and INVOKANA, respectively [see Warnings and Precautions]. In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and INVOKANA, respectively. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions]. Hypoglycemia: In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented

INVOKANA® (canagliflozin) tablets

(any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Information], episodes of hypoglycemia Studies (14) in full Prescribing Information] occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions] Precautions].

Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean percent change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% Information] with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean percent change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information] Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-HighDensity Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebocontrolled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions] Precautions]. Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. Decreases in Bone Mineral Density: Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.3) in full Prescribing Information]. At 2 years, patients randomized to INVOKANA 100 mg and INVOKANA 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both INVOKANA doses and 0.4% at the distal forearm for patients randomized to INVOKANA 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to INVOKANA 100 mg was 0%. DRUG INTERACTIONS UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information] Information]. Digoxin: There was an increase in the AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be Information] monitored appropriately. Positive Urine Glucose Test: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

Table 4: Incidence of Hypoglycemia* in Controlled Clinical Studies Monotherapy (26 weeks) Overall [N (%)] In Combination with Metformin (26 weeks)

BLEED:11.5”

TRIM:10.5”

SAFETY:9.5”

Overall [N (%)] Severe [N (%)]† In Combination with Metformin (52 weeks) Overall [N (%)] Severe [N (%)]† In Combination with Sulfonylurea (18 weeks) Overall [N (%)] In Combination with Metformin + Sulfonylurea (26 weeks) Overall [N (%)] Severe [N (%)]† In Combination with Metformin + Sulfonylurea (52 weeks) Overall [N (%)] Severe [N (%)]† In Combination with Metformin + Pioglitazone (26 weeks) Overall [N (%)] In Combination with Insulin (18 weeks) Overall [N (%)] Severe [N (%)]†

Placebo (N=192) 5 (2.6) Placebo + Metformin (N=183)

INVOKANA 100 mg (N=195) 7 (3.6) INVOKANA 100 mg + Metformin (N=368)

INVOKANA 300 mg (N=197) 6 (3.0) INVOKANA 300 mg + Metformin (N=367)

3 (1.6) 0 (0) Glimepiride + Metformin (N=482) 165 (34.2) 15 (3.1) Placebo + Sulfonylurea (N=69) 4 (5.8) Placebo + Metformin + Sulfonylurea (N=156) 24 (15.4) 1 (0.6) Sitagliptin + Metformin + Sulfonylurea (N=378) 154 (40.7) 13 (3.4) Placebo + Metformin + Pioglitazone (N=115) 3 (2.6)

16 (4.3) 1 (0.3) INVOKANA 100 mg + Metformin (N=483) 27 (5.6) 2 (0.4) INVOKANA 100 mg + Sulfonylurea (N=74) 3 (4.1) INVOKANA 100 mg + Metformin + Sulfonylurea (N=157) 43 (27.4) 1 (0.6)

INVOKANA 100 mg + Metformin + Pioglitazone (N=113) 3 (2.7)

17 (4.6) 1 (0.3) INVOKANA 300 mg + Metformin (N=485) 24 (4.9) 3 (0.6) INVOKANA 300 mg + Sulfonylurea (N=72) 9 (12.5) INVOKANA 300 mg + Metformin + Sulfonylurea (N=156) 47 (30.1) 0 INVOKANA 300 mg + Metformin + Sulfonylurea (N=377) 163 (43.2) 15 (4.0) INVOKANA 300 mg + Metformin + Pioglitazone (N=114) 6 (5.3)

Placebo (N=565) 208 (36.8) 14 (2.5)

INVOKANA 100 mg (N=566) 279 (49.3) 10 (1.8)

INVOKANA 300 mg (N=587) 285 (48.6) 16 (2.7)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Bone Fracture: The occurrence of bone fractures was evaluated in a pool of nine clinical trials with a mean duration of exposure to INVOKANA of 85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4, and 1.5 per 100 patient-years of exposure in the comparator, INVOKANA 100 mg, and INVOKANA 300 mg groups, respectively. Fractures were observed as early as 12 weeks after treatment initiation and were more likely to be low trauma (e.g., fall from no more than standing height), and affect the upper extremities [see Warnings and Precautions]. Laboratory and Imaging Tests: Tests Increases in Serum Potassium In a pooled population of patients (N=723) with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m2), increases in serum potassium to greater than 5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with INVOKANA 100 mg, and 1.3% of patients treated with INVOKANA 300 mg. In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions and Use in Specific Populations].

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INVOKANA® (canagliflozin) tablets

USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Information]. Toxicology (13.2) in full Prescribing Information] These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother Information]. [see Nonclinical Toxicology (13.2) in full Prescribing Information] Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information] Information]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions] Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). Renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information These patients had less overall glycemic efficacy and had a Information]. higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2). Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in this trial. Increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively [see Dosage and Administration (2.2) in full Prescribing Information Information, Warnings and Precautions, and Adverse Reactions]. The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information] Information]. Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information] Information]. OVERDOSAGE There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed. Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time. Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination. Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible. Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother. Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine. Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions] Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake. Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings Precautions]. and Precautions] Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions] Precautions]. Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians. Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur. Bone Fracture: Inform patients that bone fractures have been reported in patients taking INVOKANA. Provide them with information on factors that may contribute to fracture risk. Active ingredient made in Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Finished product manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Licensed from Mitsubishi Tanabe Pharma Corporation © 2013 Janssen Pharmaceuticals, Inc. 038585-150812

Once patients are started on a statin, it’s important to monitor adherence and efficacy.” —Rodica Pop-Busui, MD, PhD

“When considering treatments for lipids in patients with diabetes, use of statins should be considered based on each person’s unique characteristics,” says Dr. Pop-Busui. “Some patients may be candidates for statins, whereas others may require other cholesterol-lowering drugs. Close monitoring is required to see how their lipid levels react to medications, and adjustments in therapy might be required. In addition, lifestyle interventions should be tailored to each patient with diabetes. The

Statins, Lipid Monitoring, & Diabetes Table 2

The table below depicts recommended statin dosing and lipid monitoring strategies for patients with diabetes based on age and risk factors:

<40 years

Age

40-75 years

Research has shown that combining statins and fibrates may be effective for the treatment of LDL and HDL cholesterol and triglycerides, but this combination has been associated with risks for other complications. Combination therapy with statins and fibrates has not been shown to reduce rates of fatal cardiovascular events and non-fatal heart attacks or strokes when compared with statin monotherapy. Combination therapy using statins and niacin is not recommended because of the lack of efficacy on major CVD outcomes and because of the potential to increase risks for ischemic stroke as well as other side effects.

key is to take a patient-centered approach and strive to ensure that patients are adhering to treatment regimens appropriately in order to improve cardiovascular health and reduce risks of future cardiovascular events.”

>75 years

Considering Combination Therapy

Risk Factors

Recommended Statin Dose*

Monitoring With Lipid Panel

None

CVD risk factor(s)**

Moderate or high

Overt CVD***

High

Annually or as needed to monitor adherence

None

Moderate

CVD risk factors

High

Overt CVD

High

None

Moderate

CVD risk factors

Moderate or high

Overt CVD

High

As needed to monitor adherence

* In addition to lifestyle therapy. ** CVD risk factors include LDL cholesterol ≥100 mg/dL, high blood pressure, smoking, and overweight and obesity. *** Overt CVD includes those with previous cardiovascular events or acute coronary syndromes. Abbreviation: CVD, cardiovascular disease. Source: Adapted from: American Diabetes Association. Diabetes Care. 2015;38:S49-S57.

Rodica Pop-Busui, MD, PhD, has indicated to Physician’s Weekly that she has or has had no financial interests to report. Readings & Resources American Diabetes Association. Standards of Medical Care in Diabetes—2015. Cardiovascular Disease and Risk Management. Diabetes Care. 2015;38:S49-S57. Available at: http://care. diabetesjournals.org/content/38/Supplement_1/S49.full. | American Diabetes Association. Standards of Medical Care in Diabetes—2015. Diabetes Care. 2014;38:S1-S93. Available at: http:// professional.diabetes.org/admin/UserFiles/0%20-%20Sean/Documents/January%20Supplement%20Combined_Final.pdf. | Solano MP, Goldberg RB. Lipid management in type 2 diabetes. Clin Diabetes. 2006;24:27-32. Available at: http://clinical.diabetesjournals.org/content/24/1/27.full. | Mihaylova B, Emberson J, Blackwell L, et al, Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581-590. | Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD004816.

visit www.physiciansweekly.com 23

Mental Health

& Diabetes When mental health comorbidities of diabetes go undiagnosed and untreated, there can be significant consequences for patients. Efforts are needed to better identify and treat patients with diabetes who have mental health comorbidities.

tudies have shown that patients living with diabetes are at increased risk for developing depression, anxiety, and eating disorders, among other mental health problems. “Mental health Mark Peyrot, PhD comorbidities of diabetes can compromise adherence to diabetes treatments, which in turn can increase risks for serious short- and long-term complications,” says Mark Peyrot, PhD. Failure to adhere to 24

diabetes medication regimens can result in the development of cardiovascular disease, stroke, blindness, amputations, and cognitive decline. It can also decrease quality of life and increase risks for premature death. When mental health comorbidities of diabetes go undiagnosed and untreated, the financial cost to society and healthcare systems is substantial, and health outcomes for patients are also impacted. “Among the wide-ranging comorbidities associated with diabetes, mental health issues are among the most overlooked,” Dr. Peyrot says. “This remains

This Physician’s Weekly feature on mental health comorbidities and diabetes was completed in cooperation with the experts at the American Diabetes Association.

true despite the potential of mental health problems to compromise self-management and increase risks for serious complications.” Studies indicate that only about one-third of patients with these coexisting mental health conditions receive a diagnosis and treatment for them.

Depression, Anxiety, & Eating Disorders Major depressive disorder affects nearly 7% of all adults in the United States and is more likely to be diagnosed in people with diabetes. “Diabetes is a

risk factor for depression, and depression is a risk factor for diabetes,” Dr. Peyrot says. Depression among patients with diabetes has been linked to poor self-care, poor glycemic control, more longterm complications, and a decreased quality of life. Fortunately, depression can be successfully treated in people with diabetes using collaborative care models that involve psychotherapy and antidepressants. These treatments can improve depressive symptoms and may have a positive effect on glycemic control. Many patients with diabetes also have comorbid visit www.physiciansweekly.com 25

Screening for Psychosocial Problems

to persist and worsen over time and can lead to cascading complications and worsening disease.

The American Diabetes Association has issued the following statements regarding the screening of patients with diabetes for psychosocial problems:

Screenings Matter

Table 1

Times when patients are likely to exhibit psychological vulnerability and should be assessed include, but are not limited to: • At diagnosis. • When the need for intensified treatment is evident.

• When medical status changes. • When complications are discovered.

Diabetes-related distress is distinct from clinical depression and should be assessed on a routine basis among people with diabetes and their family members. • Significant diabetes-related distress has been reported in almost half of patients, but only about one-quarter reported that their healthcare team asked them how diabetes impacted their life. High levels of distress are significantly linked to poor A1C, dietary and exercise behaviors, and medication taking. • These outcomes are indications of the need for increased attention to psychological issues. Other issues known to impact diabetes outcomes that should be assessed include, but are not limited to: • Attitudes about the illness. • Expectations for medical management. • Expectations for outcomes.

• Anxiety. • G eneral and diabetesrelated quality of life. • R esources (financial, social, and emotional). • Psychiatric history.

Various screening tools are available for different components of psychosocial status. Source: Adapted from: American Diabetes Association. Diabetes Care. 2014;37(suppl):S14-S80.

anxiety disorders, such as generalized anxiety disorder, panic disorder, or PTSD. “Some of these disorders may occur in conjunction with depression,” explains Dr. Peyrot. Some studies show that eating disorders are a problem for women with type 1 diabetes, but less is known about these conditions in men with diabetes. “Patients with disturbed eating behaviors often purge through insulin restriction,” says Dr. Peyrot. Like the other mental health conditions, eating disorders tend 26

According to standards of care from the American Diabetes Association, people with diabetes should be treated by a multidisciplinary medical team. Physicians are also recommended to routinely screen for psychosocial problems, including depression and diabetes-related distress, anxiety, eating disorders, and cognitive impairment (Table 1). “Physicians often do not assess or manage mental health conditions until they become severe,” Dr. Peyrot says. “It’s important that physicians routinely assess diabetes-specific psychological factors that increase risk for mental health disorders and poor diabetes outcomes—such as fear of hypoglycemia and complications, difficulties with diabetes self-management, and lack of practical and emotional support—and support patients in their efforts to overcome these barriers to effective self-management. Despite these barriers, there are simple steps clinicians can take to assess and support their patients.” When physician support is not sufficient to manage emerging psychological issues, formal screening is recommended, along with referral to or consultation with mental health specialists. In addition to patients with poor diabetes outcomes, studies suggest that diabetes patients who are at greatest risk of mental health issues are those who are considered most vulnerable within any chronic disease. This includes people with: • Limited access to good healthcare. • Limited resources and education. • Limited family and social support. • Multiple life stressors in addition to a chronic disease.

Many mental health comorbidities of diabetes are treatable, but it is critical that timely referrals are made to mental health providers for diagnosis and treatment.” —Mark Peyrot, PhD

Referring Patients “Many mental health comorbidities of diabetes are treatable, but it is critical that timely referrals are made to mental health providers for diagnosis and treatment,” Dr. Peyrot says (Table 2). He adds that clinicians should recognize the importance of screening patients for these conditions early so that they will be more likely to be referred to mental health teams at a time when they can provide effective treatment for those problems. Considering the vast burden of diabetes, identifying and treating mental health comorbidities among patients with diabetes should be a priority, according to Dr. Peyrot. “The high prevalence and costs of mental health and diabetes, combined with evidence that behavioral factors are important for effective diabetes selfcare, create an important opportunity,” he says. “Mental health screening and treatment need to be integrated into multidisciplinary diabetes care teams in order to improve outcomes and decrease healthcare expenditures.”

Referral to Mental Health Specialists Table 2

Below are recommendations from the American Diabetes Association regarding the referral to or consultation with mental health specialists: Indications for referral to or consultation with a mental health specialist familiar with diabetes management include, but are not limited to: • Gross disregard for the • P ossibility of self-harm. medical regimen • Debilitating anxiety (alone (by self or others). or with depression). • Depression. • Cognitive functioning • Indications of an that significantly impairs eating disorder. judgment. It is preferable to incorporate psychological assessment and support into routine care rather than to wait for a specific problem or deterioration in metabolic or psychological status. Although the clinician may not feel qualified to treat psychological problems, using the patient-provider relationship as a foundation can increase the likelihood that the patient will accept referral for other services. Collaborative care interventions and use of a team approach have demonstrated efficacy in diabetes and depression. Interventions to enhance self-management and address severe distress have demonstrated efficacy in reducing diabetes-related distress. Source: Adapted from: American Diabetes Association. Diabetes Care. 2014;37(suppl):S14-S80.

Mark Peyrot, PhD, has indicated to Physician’s Weekly that he has served on the advisory panel for Eli Lilly, GlaxoSmithKline, Novo Nordisk, and Tethys. He has also served as a consultant for Calibra Medical, Eli Lilly, and Novo Nordisk, and has received grants/ research aid from AstraZeneca, Eli Lilly, Genentech, and Novo Nordisk. Readings & Resources Ducat L, Philipson LH, Anderson BJ. The mental health comorbidities of diabetes. JAMA. 2014;312:691-692. Available at: http://jama.jamanetwork.com/article.aspx?articleid=1888681. | American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl):S14-S80. | Kessler RC, ChiuWT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication Arch Gen Psychiatry. 2005;62:617-627. | Egede LE, Zheng D, Simpson K. Comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. Diabetes Care. 2002;25:464-470. | Anderson BJ, Mansfield AK. Psychological issues in the treatment of diabetes. In: Beaser RS, ed. Joslin’s Diabetes Deskbook. 2nd ed. Boston, MA: Joslin Diabetes Center; 2007:641-661.

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