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Therapeutics Bulletin

October 2018

Please see Important Safety Information throughout. Please see accompanying Prescribing Information, including Boxed Warning. Table of contents Introduction Introduction page 2 is a complex that has the potential to negatively influence the health of patients if left untreated. and page 3 Currently, about 30 million people in the United States have diabetes (including about 7 million undiagnosed Introduction to Victoza® page 4 cases), which represents about 9.4% of the U.S. population. Approximately 90-95% of those cases are patients with LEADER Trial page 5 type 2 diabetes. Almost 34% of the population has pre- diabetes (based on elevated fasting or A1C levels), Additional features page 10 meaning they are at risk for developing type 2 diabetes.1 Complications associated with type 2 diabetes can lead to Summary page 10 increased emergency room visits, hospitalizations, and even death.1 For these reasons, treatment of type 2 diabetes and References page 12 its associated complications is an important topic of study.

Among other complications, patients with type 2 diabetes often experience cardiovascular disease (CVD). One therapy used to treat type 2 diabetes is Victoza® (liraglutide) injection 1.2 mg or 1.8 mg a human - PUBLISHER ASSISTANT ART DIRECTOR like -1 (GLP-1) analog that was approved by the Gene Conselyea John Salesi U.S. Food and Drug Administration on January 25, 2010, WRITER/EDITOR PROJECT MANAGER as an adjunct to diet and exercise, to improve glycemic Jaelithe Russ Aubrey Feeley control in adults with type 2 diabetes. On August 27, 2017, Francine Pozzolano The U.S. Food and Drug Administration approved Victoza® ART DIRECTOR (liraglutide) injection to reduce the risk of major adverse Ari Mihos SALES Ron Gordon cardiovascular (CV) events including non fatal myocardial infarction (MI), non fatal , or CV death, in adults with type 2 diabetes and established CV disease.2

The landmark LEADER trial demonstrated that Victoza® significantly reduced the risk of major adverse cardiovascular events, a three component composite 630 Madison Avenue endpoint consisting of cardiovascular death, non-fatal 2nd Floor MI, or non-fatal stroke, by 13% vs placebo (hazard ratio, Manalapan, NJ 07726 0.87; 95% confidence interval, 0.78-0.97; p=0.01) with an absolute risk reduction (ARR) of 1.9%.2 This bulletin ©2018 American Medical Communications, Inc, Manalapan, NJ 07726. 18061 provides information on the connection between type 2 diabetes and CVD; indications, use, and safety information for Victoza®; and the LEADER trial.

Important Safety Information Contraindications Warnings and Precautions • Victoza ® is contraindicated in patients with a personal or • Risk of C-cell Tumors: Patients should be family history of MTC or in patients with MEN 2, and in referred to an endocrinologist for further evaluation if patients with a prior serious reaction to serum calcitonin is measured and found to be elevated Victoza® or to any of the product components. Serious or thyroid nodules are noted on physical examination or hypersensitivity reactions including anaphylactic reactions neck imaging. and angioedema have been reported with Victoza®.

2 Victoza® Product Bulletin Background on disease

Type 2 diabetes Selected Important Safety Information According to the American Diabetes Association, “Diabetes is a complex, chronic illness requiring continuous medical care with multifactorial risk-reduction WARNING: RISK OF THYROID C-CELL TUMORS strategies beyond glycemic control.”3 Patients with type • Liraglutide causes dose-dependent and treat- 2 diabetes often present with multiple, related health ment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats concerns. Nearly half of patients with type 2 diabetes are ® above the target A1C of <7% 4 and approximately 85% and mice. It is unknown whether Victoza causes are also classified as obese or .5 In addition, thyroid C-cell tumors, including medullary thyroid studies have shown that adults with type 2 diabetes are carcinoma (MTC), in humans, as the human rele- up to four times more likely to develop cardiovascular vance of liraglutide-induced rodent thyroid C-cell disease, which is the number one leading cause of tumors has not been determined. morbidity and mortality in patients with diabetes.6,7 • Victoza® is contraindicated in patients with a Residual CV risk personal or family history of MTC and in patients Some of the key factors in diabetes care include lifestyle with Multiple Endocrine Neoplasia syndrome type 3 2 (MEN 2). Counsel patients regarding the potential changes, monitoring, glycemic control, and medication . ® The addition of high-dose statins to type 2 diabetes risk for MTC with the use of Victoza and inform care can also reduce the risk of vascular complications.8 them of symptoms of thyroid tumors (eg, a mass However, when patients are treated with the optimal in the neck, dysphagia, dyspnea, persistent hoarse- standards of CV risk reduction and diabetes care, including ness). Routine monitoring of serum calcitonin or intensive therapy and multifactorial management, there using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with is still a residual risk (around 14% with high-dose statin ® treatment) for CVD.9 Victoza .

The Treating to New Targets (TNT) study was designed to Indications and Limitations of Use investigate whether the benefits of high-dose intensive Victoza® (liraglutide) injection 1.2 mg or 1.8 mg is indicat- atorvastatin therapy could be achieved in patients ed as an adjunct to diet and exercise to improve glycemic with CHD and diabetes. 1,501 patients with diabetes control in adults with type 2 diabetes mellitus, and to and CHD, with LDL cholesterol levels of <130 mg/dl, reduce the risk of major adverse cardiovascular (CV) events were randomized to double-blind therapy with either (CV death, non-fatal myocardial infarction, or non-fatal atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. While the stroke) in adults with type 2 diabetes mellitus and estab- study did show clinical benefit, even with high-dose statin lished CV disease. treatment 14% of the patients studied experienced CV • Victoza® is not a substitute for and should not be 3,9,10 events. used in patients with mellitus or diabetic . Ultimately, there is a need to consider the residual CV risk • Concurrent use with prandial insulin has not been when treating patients with type 2 diabetes. studied.

Warnings and Precautions (cont’d) • : Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with Victoza® post-marketing. Observe patients carefully for of pancreatitis (persistent severe , sometimes radiating to the back with or without vomiting). If pancreatitis is suspected, discontinue Victoza® promptly and if pancreatitis is confirmed, do not restart. Victoza® has been studied in a limited number of patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at a higher risk for development of pancreatitis on Victoza®.

Please see additional Important Safety Information throughout. Please see accompanying Prescribing Information, including Boxed Warning.

Victoza® Product Bulletin 3 Clinical Background For patients with type 2 diabetes and established CVD, Mechanism of Action2 Victoza® (liraglutide) injection 1.2 mg or 1.8 mg is a GLP-1 RA Liraglutide is an acylated human Glucagon-Like Peptide-1 therapy approved to improve glycemic control and reduce (GLP-1) agonist with 97% sequence the risk of major adverse cardiovascular events.2 homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Victoza® is a glucagon−like peptide−1 (GLP−1) receptor Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a agonist that can help manage CVD risk for adult patients membrane-bound cell-surface receptor coupled to adenylyl with type 2 diabetes and established CVD. It is indicated cyclase by the stimulatory G-protein, Gs, in pancreatic beta as an adjunct to diet and exercise to improve glycemic cells. Liraglutide increases intracellular cyclic AMP (cAMP) control in adults with type 2 diabetes mellitus, and to leading to insulin release in the presence of elevated reduce the risk of major adverse cardiovascular events glucose concentrations. This insulin secretion subsides (cardiovascular death, non-fatal myocardial infarction, or as blood glucose concentrations decrease and approach non-fatal stroke) in adults with type 2 diabetes mellitus euglycemia. Liraglutide also decreases glucagon secretion and established cardiovascular disease.2 Victoza® is also a in a glucose-dependent manner. The mechanism of blood first-line treatment option. glucose lowering also involves a delay in gastric emptying.

Limitations of Use: Common adverse reactions2 • Not for treatment of type 1 diabetes mellitus or diabetic Table 1 shows common adverse reactions, excluding ketoacidosis. , associated with the use of Victoza®. These • Has not been studied in combination with prandial adverse reactions occurred more commonly with Victoza® insulin. than with placebo and occurred in at least 5% of patients treated with Victoza®.

Table 1: Adverse reactions reported in ≥ 5% of Victoza®-treated patients2 Placebo Liraglutide 1.2 mg Liraglutide 1.8 mg N = 661 N = 645 N = 1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5

Important Safety Information (cont’d) Warnings and Precautions (cont’d) • Never Share a Victoza® Pen Between Patients, even • Renal Impairment: Acute renal failure and worsening if the needle is changed. Pen-sharing poses a risk for of chronic renal failure, which may sometimes require transmission of blood-borne pathogens. hemodialysis, have been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or • Hypoglycemia: When Victoza® is used with an insulin dehydration. Use caution when initiating or escalating secretagogue (eg, a sulfonylurea) or insulin, serious doses of Victoza® in patients with renal impairment. hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

4 Victoza® Product Bulletin Clinical studies Clinical studies Key inclusion and exclusion criteria12 In glycemic control trials, Victoza® (liraglutide) injection The LEADER trial enrolled two populations of high- 1.2 mg or 1.8 mg has been studied as monotherapy and in risk patients. Patients with prior CHD or CKD (80% of combination with one or two oral anti-diabetic medications the enrolled population) were 50 years of age or older or basal insulin. In each of the placebo controlled trials, and had one or more of the following cardiovascular treatment with Victoza® produced clinically and statistically comorbidities: concomitant cerebrovascular disease, significant improvements in hemoglobin A1C (primary peripheral vascular disease, chronic heart failure, or endpoint) and fasting plasma glucose (FPG) (secondary chronic disease. Patients without CVD (20% of the endpoint) compared to placebo.2 Victoza® was also studied in enrolled population) were 60 years of age or older and a cardiovascular outcomes trial, known as the LEADER trial. had other specified risk factors for cardiovascular disease, as listed in Table 2. LEADER trial – a landmark cardiovascular outcomes trial for Victoza®11

Study Design12 A phase 3B, multicenter, international, randomized, double-blind, placebo-controlled study to assess the cardiovascular safety of Victoza®. Patients with type 2 diabetes at high risk for cardiovascular events (N=9340) were randomized to receive once-daily Victoza® (0.6 mg – 1.8 mg QD with all patients being titrated to 1.8 mg QD or maximum-tolerated dose), or placebo. The primary endpoint was the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The trial was prospectively designed and powered to assess whether Victoza® was noninferior when measuring effect on CV events. If confirmed to be noninferior the trial prespecified testing for superiority over standard of care. Patients received trial products in addition to standard of care treatments such as oral antidiabetic treatments, insulin, and antihypertensive, antiplatelet, and lipid- lowering therapies.

Figure 1: Most commonly used standard of care agents1,2

CV Diabetes

Statins 72.2% 76.5%

Aspirin 9% Insulin treatment 44.6%

Beta blockers 55.5% Sulfonylurea 50.7%

ACE Inhibitors 51.0%

92.4% of patients were on antihypertensives1 68.7% of patients were on multiple antidiabetic medications1

Warnings and Precautions (cont’d) • Hypersensitivity Reactions: Serious hypersensitivity reactions (eg, and angioedema) have been reported post- marketing. If symptoms of hypersensitivity reactions occur, patients must stop taking Victoza®; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity reaction to Victoza®. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-receptor agonist because it is unknown whether such patients will be predisposed to these reactions with Victoza®. Please see additional Important Safety Information throughout. Please see accompanying Prescribing Information, including Boxed Warning.

Victoza® Product Bulletin 5 Clinical studies, continued

Table 2: LEADER Inclusion and Exclusion Criteria12 Inclusion Criteria • Type 2 diabetes • Anti-diabetic drug naïve or treated with one or more oral anti-diabetic drugs or treated with human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with OAD(s) • HbA1C ≥7.0% • Prior CVD or CKD cohort: age ≥50 and ≥1 of the following criteria. • Prior MI • Prior stroke or TIA • Prior coronary, carotid or peripheral arterial revascularization • >50% stenosis of coronary, carotid, or lower extremity arteries • History of symptomatic CHD documented by Positive exercise stress test or any cardiac imaging or Unstable angi- na with ECG changes • Asymptomatic cardiac ischemia Documented by positive nuclear imaging test, exercise test or dobutamine stress echo • Chronic heart failure NYHA class II-III • Chronic eGFR 15-59 cc/minute per 1.73 m2 by MDRD or Cockroft-Gault formula • No Prior CVD group: Age ≥60 y and ≥1 of the following criteria. • Microalbuminuria or proteinuria • Hypertension and left ventricular hypertrophy by ECG or imaging • Left ventricular systolic or diastolic dysfunction by imaging • Ankle-brachial index <0.9 Exclusion Criteria • Type 1 diabetes • Calcitonin ≥50 ng/L • Use of a GLP-1 receptor agonist (exenatide, liraglutide or other) or pramlintide or any DPP-4 inhibitor within the 3 months prior to screening • Use of insulin other than human NPH insulin or long-acting insulin analogue or premixed insulin within 3 months prior to screening. Short-term use of other insulin during this period in connection with intercurrent illness is al- lowed, at Investigators discretion • Acute decompensation of glycemic control • An acute coronary or cerebrovascular event in the previous 14 d • Currently planned coronary, carotid, or peripheral artery revascularization • Chronic heart failure (NYHA class IV) • Current continuous renal replacement therapy • End-stage liver disease • History of solid organ transplant or awaiting solid organ transplant • Malignant neoplasm • Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC) • Personal history of non-familial medullary thyroid carcinoma

Important Safety Information (cont’d) Warnings and Precautions (cont’d) Adverse Reactions • Acute Gallbladder Disease: In the LEADER trial, 3.1% of • The most common adverse reactions, reported in ≥5% of Victoza® (liraglutide) injection vs. 1.9% of placebo-treated patients treated with Victoza® and more commonly than patients reported an acute event of gallbladder disease, in patients treated with placebo, are nausea, diarrhea, such as cholelithiasis or cholecystitis. The majority of events headache, vomiting, decreased appetite, dyspepsia, and required hospitalization or cholecystectomy. If cholelithiasis constipation. Immunogenicity-related events, including is suspected, gallbladder studies and appropriate clinical urticaria, were more common among Victoza®-treated follow up are indicated. patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

6 Victoza® Product Bulletin LEADER trial baseline demographics and to III heart failure in 14% disease characteristics2 • Mean eGFR at baseline 79 mL/min/1.73 m2 At baseline, demographic and disease characteristics were • 41.8% of patients had mild renal impairment (eGFR balanced: 60 to 90 mL/min/1.73 m2), 20.7% moderate renal • Mean age of 64 years impairment (eGFR 30 to 60 mL/min/1.73 m2), 2.4% severe • 64.3% male renal impairment (eGFR < 30 mL/ min/1.73 m2) • 77.5% Caucasian • 10.0% Asian LEADER trial results • 8.3% African American Victoza® (liraglutide) injection reduced the relative risk • 12.1% identified as Hispanic or Latino of major adverse cardiovascular events (MACE) by 13%, • Mean duration of type 2 diabetes was 12.8 years as shown in figure 2, and ARR was reduced by 1.9%. • Mean HbA1C of 8.7% Components of the composite primary endpoint included CV • Mean BMI of 32.5 kg/m2 death, nonfatal MI, or nonfatal stroke.2,11 • History of previous myocardial infarction reported in 31% • Prior revascularization procedure in 39% For the primary analysis, a Cox proportional hazards • Prior ischemic stroke in 11% model was used to test for non-inferiority against the • Documented symptomatic coronary disease in 9% pre-specified risk margin of 1.3 for the hazard ratio • Documented asymptomatic cardiac ischemia in 26% of MACE and to test for superiority on MACE if non- • Diagnosis of New York Heart Association (NYHA) class II inferiority was demonstrated.2

Figure 2: Time to first occurrence of MACE in the LEADER trial11

Victoza® + placebo + standard of care standard of care 20

15 13% 10 RRR OVERALL MACE n=608 (P=0.01) 5

Patients with a first CV event (%) 0 0 6 12 18 24 30 36 42 48 54 Absolute risk reduction Months since randomization 1.9%

Median time of exposure to treatment: 3.5 years. The primary composite outcome occurred in fewer Median daily dose of Victoza®: 1.78 mg. patients in the Victoza® group (608 of 4668 patients [13.0%]) than in the standard of care group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78-0.97; P=0.01).

Drug Interactions Use in Specific Populations • Victoza® causes a delay of gastric emptying and has the • Victoza® has not been studied in patients with type 2 potential to impact the absorption of concomitantly diabetes below 18 years of age and is not recommended administered oral medications. Caution should be for use in pediatric patients. exercised when oral medications are concomitantly • Victoza® slows gastric emptying. Victoza® has not been administered with Victoza®. studied in patients with pre-existing . • Victoza® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Please see additional Important Safety Information throughout. Please see accompanying Prescribing Information, including Boxed Warning.

Victoza® Product Bulletin 7 Clinical studies, continued • Median time of exposure to treatment: 3.5 years. In the LEADER trial, Victoza® (liraglutide) injection • Median daily dose of Victoza® (liraglutide) injection: demonstrated a life-saving benefit - a prespecified 1.78 mg. secondary endpoint 2,11 • The primary composite outcome occurred in fewer Vital status was available for 99.7% of subjects in patients in the Victoza® group (608 of 4668 patients the trial. A total of 828 deaths were recorded during [13.0%]) than in the standard of care group (694 of 4672 the LEADER trial. A majority of the deaths in the [14.9%]) (hazard ratio, 0.87; 95% confidence interval trial were categorized as cardiovascular deaths. All [CI], 0.78-0.97; P=0.01). non-cardiovascular deaths were balanced between the treatment groups (3.5% in patients treated with Primary composite endpoint component results Victoza® and 3.6% in patients treated with placebo). Results for all three components of the primary composite The estimated hazard ratio of time to all-cause death for endpoint supported the use of Victoza® versus standard of Victoza® compared to placebo was 0.85 (0.74, 0.97).2 care alone (see figure 3).11 Among patients with type 2 diabetes who were at high risk for cardiovascular events while they were taking standard therapy, those in the liraglutide group had lower rates of cardiovascular events and death from any cause than did those in the placebo group (see figure 4).2

Figure 3: Primary composite Endpoint Results — Victoza® versus Standard of Care11

FAVORS FAVORS HAZARD RATIO (95% CI) VICTOZA® STANDARD OF CARE CV DEATH 0.78 (0.66; 0.93)

NONFATAL MI 0.88 (0.75; 1.03)

NONFATAL STROKE 0.89 (0.72; 1.11)

1

Indications and Limitations of Use Victoza® (liraglutide) injection 1.2 mg or 1.8 mg is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, and to reduce the risk of major adverse cardiovascular (CV) events (CV death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established CV disease. • Victoza ® is not a substitute for insulin and should not be used in patients with type 1 diabetes mellitus or . • Concurrent use with prandial insulin has not been studied.

8 Victoza® Product Bulletin Prespecified secondary endpoints Patients with renal impairment • Death from CV causes occurred in fewer patients in Given that nearly 40% of patients with type 2 diabetes the Victoza® (liraglutide) injection group (219 patients may develop renal impairment,13 Victoza® was also [4.7%]) than in the standard of care group (278 [6.0%]) studied in patients with mild to severe renal impairment (hazard ratio: 0.78; 95% CI; 0.66-0.93). (mild renal impairment=eGFR 60 to ≤89 mL/min/1.73m2; • Death from all causes occurred in fewer patients in the moderate renal impairment=eGFR 30-59 mL/min/1.73m2, Victoza® group (381 patients [8.2%]) than in the standard severe renal impairment=eGFR 15-29 mL/min/1.73m2). of care group (447 patients [9.6%]) (hazard ratio: 0.85; 95% CI, 0.74-0.97). In the LEADER trial, no overall differences in safety or • Death from CV causes was a prespecified secondary efficacy were seen in patients with mild, moderate, or endpoint. severe renal function compared to those with normal • Hazard ratio: 0.78 (95% CI, 0.66-0.93). renal function,11 and no dosage adjustments were • Median time of exposure to treatment: 3.5 years. recommended. • Median daily dose of Victoza®: 1.78 mg.

Figure 4: Death from CV causes (prespecified secondary endpoint)11

Victoza® + placebo + standard of care standard of care 7.5

5.5 22% 3.5 RRR CV DEATH n=219 1.5

Patients with a first CV event (%) 0 0 6 12 18 24 30 36 42 48 54 Absolute risk reduction 1.3% Months since randomization Prespecified secondary endpoint: Death from CV causes occurred in fewer patients in the Victoza® group (219 patients [4.7%]) than in the standard of care group (278 [6.0%]) (hazard ratio, 0.78, 95% CI; 0.66-0.93).

Prespecified secondary endpoint: Death from CV causes occurred in fewer ALL-CAUSE DEATH patients in the Victoza® group (381 15% RRR n=381 patients [8.2%]) than in the standard of care group (447 [9.6%]) (hazard ratio, 0.85, 95% CI; 0.74-0.97). Absolute risk reduction 1.4%

Please see additional Important Safety Information throughout. Please see accompanying Prescribing Information, including Boxed Warning.

Victoza® Product Bulletin 9 Clinical studies, continued

It should be noted that there is limited experience with (B) ® Mean fasting plasma glucose (FPG) values Victoza in patients with end stage renal disease. There (secondary endpoint) have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may 200 200 sometimes require hemodialysis. Victoza® has not been 180 180 found to be directly nephrotoxic in animal studies or FPG (mg/dl) clinical trials. There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, 160 160 which may sometimes require hemodialysis in Victoza®- treated patients. Some of these events were reported 140 140 in patients without known underlying renal disease. FPG (mg/dl) A majority of the reported events occurred in patients 120 120 who had experienced nausea, vomiting, diarrhea, or 0 0 dehydration. 0 4 10 16 22 28 34 40 46 52 Time (weeks) Other clinical trial results In addition to CV risk reduction, Victoza® (liraglutide) injection has demonstrated powerful A1C reductions (C) Mean change in body weight (secondary endpoint) across multiple clinical trials with the additional benefit of and low rates of hypoglycemia. Victoza® Time (weeks) is not indicated for chronic , and 0 4 10 16 22 28 34 40 46 52 weight change was a secondary endpoint in clinical 0 trials. The Pratley extension trial compared the efficacy and safety of once-daily Victoza® 1.8 mg with dipeptidyl -2.2 peptidase-4 inhibitor sitagliptin 100 mg, each added to metformin, over 52 weeks in individuals with type 2 -4.4 diabetes (prior trials had ended at 26 weeks). In this trial, 26-week improvements were sustained after 52 weeks -6.6 of treatment, with Victoza® producing significantly -8.8 greater glycemic and weight reductions than sitagliptin. The results of the Pratley extension trial can be found in 14 -11 figure 5. Change in body weight (lbs.)

Figure 5: Effect of 1.2 mg liraglutide, 1.8 mg liraglutide or 100 mg sitagliptin on glycemic control and body weight Key takeaways from baseline to 52 weeks. Error bars are 1.96 • SE, corresponding to the 95% CI.14 In summary: • Among other risks and complications, patients with type 2 diabetes have an increased risk of developing cardiovascular disease (CVD). (A) Mean HbA1C values • In patients with type 2 diabetes and established CVD, ® 9.0 Liraglutide 1.2 mg Victoza is approved to help improve glycemic control and reduce the risk of major adverse cardiovascular events, Liraglutide 1.8 mg 8.5 including CV death, non-fatal MI, or non-fatal stroke. ® Sitagliptin 100 mg • Victoza is a first-line treatment option. 8.0 • In addition to CV risk reduction, Victoza® has (%)

10 demonstrated powerful A1C reductions across multiple 7.5 clinical trials with the additional benefit of weight loss HbA and low rates of hypoglycemia in glycemic efficacy 7.0 trials. Victoza® is not indicated for chronic weight management, and weight change was a secondary 0.0 endpoint in clinical trials. 0 4 10 16 22 28 34 40 46 52 Time (weeks) Please see additional Important Safety Information throughout. Please see accompanying Prescribing Information, including Boxed Warning.

10 Victoza® Product Bulletin Important Safety Information • Never Share a Victoza® Pen Between Patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. WARNING: RISK OF THYROID C-CELL TUMORS • Hypoglycemia: When Victoza® is used with an insulin • Liraglutide causes dose-dependent and treatment-du- secretagogue (eg, a sulfonylurea) or insulin, serious ration-dependent thyroid C-cell tumors at clinically hypoglycemia can occur. Consider lowering the dose of relevant exposures in both genders of rats and mice. It the insulin secretagogue or insulin to reduce the risk of is unknown whether Victoza® causes thyroid C-cell tu- hypoglycemia. mors, including medullary thyroid carcinoma (MTC), in • Renal Impairment: Acute renal failure and worsening humans, as the human relevance of liraglutide-induced of chronic renal failure, which may sometimes require rodent thyroid C-cell tumors has not been determined. hemodialysis, have been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or • Victoza ® is contraindicated in patients with a per- dehydration. Use caution when initiating or escalating sonal or family history of MTC and in patients with doses of Victoza® in patients with renal impairment. Multiple Endocrine Neoplasia syndrome type 2 (MEN • Hypersensitivity Reactions: Serious hypersensitivity 2). Counsel patients regarding the potential risk for reactions (eg, anaphylaxis and angioedema) have been MTC with the use of Victoza® and inform them of reported post-marketing. If symptoms of hypersensitivity symptoms of thyroid tumors (eg, a mass in the neck, reactions occur, patients must stop taking Victoza®; dysphagia, dyspnea, persistent hoarseness). Rou- treat promptly per standard of care, and monitor until tine monitoring of serum calcitonin or using thyroid signs and symptoms resolve. Do not use in patients ultrasound is of uncertain value for early detection with a previous hypersensitivity reaction to Victoza®. of MTC in patients treated with Victoza®. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient Indications and Limitations of Use with a history of anaphylaxis or angioedema with Victoza® (liraglutide) injection 1.2 mg or 1.8 mg is indicat- another GLP-receptor agonist because it is unknown ed as an adjunct to diet and exercise to improve glycemic whether such patients will be predisposed to these control in adults with type 2 diabetes mellitus, and to re- reactions with Victoza®. duce the risk of major adverse cardiovascular (CV) events • Acute Gallbladder Disease: In the LEADER trial, 3.1% (CV death, non-fatal myocardial infarction, or non-fatal of Victoza® vs. 1.9% of placebo-treated patients stroke) in adults with type 2 diabetes mellitus and estab- reported an acute event of gallbladder disease, lished CV disease. such as cholelithiasis or cholecystitis. The majority of • Victoza ® is not a substitute for insulin and should not be events required hospitalization or cholecystectomy. used in patients with type 1 diabetes mellitus or diabetic If cholelithiasis is suspected, gallbladder studies and ketoacidosis. appropriate clinical follow up are indicated. • Concurrent use with prandial insulin has not been studied. Adverse Reactions • The most common adverse reactions, reported in ≥5% of Contraindications patients treated with Victoza® and more commonly than ® • Victoza is contraindicated in patients with a personal or in patients treated with placebo, are nausea, diarrhea, family history of MTC or in patients with MEN 2, and in headache, vomiting, decreased appetite, dyspepsia, and patients with a prior serious hypersensitivity reaction to constipation. Immunogenicity-related events, including ® Victoza or to any of the product components. Serious urticaria, were more common among Victoza®-treated hypersensitivity reactions including anaphylactic reactions patients (0.8%) than among comparator-treated ® and angioedema have been reported with Victoza . patients (0.4%) in clinical trials.

Warnings and Precautions Drug Interactions • Risk of Thyroid C-cell Tumors: Patients should be referred to • Victoza ® causes a delay of gastric emptying and has the an endocrinologist for further evaluation if serum calcitonin potential to impact the absorption of concomitantly is measured and found to be elevated or thyroid nodules administered oral medications. Caution should be are noted on physical examination or neck imaging. exercised when oral medications are concomitantly • Pancreatitis: Acute pancreatitis, including fatal and nonfatal administered with Victoza®. hemorrhagic or necrotizing pancreatitis, has been observed ® in patients treated with Victoza postmarketing. Observe Use in Specific Populations patients carefully for signs and symptoms of pancreatitis • Victoza ® has not been studied in patients with type 2 (persistent severe abdominal pain, sometimes radiating diabetes below 18 years of age and is not recommended to the back with or without vomiting). If pancreatitis is for use in pediatric patients. suspected, discontinue Victoza® promptly and if pancreatitis • Victoza ® slows gastric emptying. Victoza® has not been is confirmed, do not restart. Victoza® has been studied in a studied in patients with pre-existing gastroparesis. limited number of patients with a history of pancreatitis. It • Victoza ® should be used during pregnancy only if the is unknown if patients with a history of pancreatitis are at a potential benefit justifies the potential risk to the fetus. higher risk for development of pancreatitis on Victoza®.

Victoza® Product Bulletin 11 References

1. American Diabetes Association. National Diabetes Statistics Report, 2017—Estimates of Diabetes and Its Burden in the United States. http://www.diabetes.org/diabetes-basics/statistics/. Accessed July 2018. 2. Victoza® (liraglutide) injection [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; 2017. 3. American Diabetes Association. Standards of Medical Care in Diabetes—2018. Diabetes Care. 2018;41(Suppl. 1):S1–S159. 4. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988–2010. Diabetes Care. 2013 Aug; 36(8): 2271–2279. 5. World Health Organization. and Overweight Fact Sheet. http://www.who.int/dietphysical activity/media/en/ gsfs_obesity.pdf. Accessed July 2018. 6. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical Update: Cardiovascular disease in diabetes mellitus: Atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus–mechanisms, management, and clinical considerations. Circulation. 2016; 133:2459-2502. 7. World Heart Federation. Cardiovascular Disease Risk Factors. Available at: www.world-heart-federation.org/ cardiovascular-health/cardiovascular-disease-risk-factors/diabetes/. Accessed July 2017. 8. Fruchart JC, Davignon J, Hermans MP, et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol. 2014;13:26. 9. Shepherd J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care. 2006;29(6):1220-6. 10. Ryden L, Grant PJ, Anker SD, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular developed in collaboration with the EASD. Eur Heart J. 2013;34(39):3035-87. 11. Marso SP, Daniels GH, Brown-Frandsen K, et al; the LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. 12. Marso SP, Poulter NR, Nissen SE, et al. Design of the liraglutide effect and action in diabetes: Evaluation of cardiovascular outcome results (LEADER) trial. Am Heart J. 2013;166(5):823-30. 13. Bailey C, Day C. Diabetes therapies in renal impairment. Br J Diabetes Vasc Dis. 2012;12(4):167-171. 14. Pratley RE, Nauck M, Bailey T, et al. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial. Int J Clin Pract;2011;65(4):397–407.

Please see additional Important Safety Information throughout. Please see accompanying Prescribing Information, including Boxed Warning.

American Medical Communications has received compensation for this communication from Novo Nordisk, the maker of Victoza®. Victoza® is a registered trademark of Novo Nordisk A/S. Novo Nordisk is a registered trademark of Novo Nordisk A/S. © 2018 Novo Nordisk All rights reserved. US18VZ00132 October 2018