Reducing Cardiovascular Risk in Patients with Type 2 Diabetes and established CVD using Evidence-Based Medicine

DECEMBER 11, 2017
This article was sponsored by Novo Nordisk.

In patients with type 2 diabetes (T2D), cardiovascular (CV) events are the leading cause of morbidity and mortality, as well as the largest contributor to direct and indirect costs.1 Because of the pronounced impact of cardiovascular disease (CVD), it is important for health care providers to address risks and recommend interventions when possible. This article will share an update regarding the findings of a clinical trial that evaluated the CV outcomes of patients with T2D and established CVD on Victoza® (liraglutide) therapy.2

Selected Safety Information
  • Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.
  • Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of Victoza® and inform them of symptoms of thyroid tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Victoza®.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in patients with diabetes. In those with T2D, CVD is estimated to occur 14.6 years earlier and with more severity than in those without T2D.3 Approximately two-thirds of deaths in patients with diabetes are attributed to cardiovascular disease. Of these CV deaths, an estimated 40% are from ischemic heart disease (IHD), 15% from other forms of heart disease, such as congestive heart failure, and approximately 10% from stroke.3 The estimated cost of CV outcomes in patients with T2D are $12,962 per patient-year of follow-up.4 Additionally, obesity increases the risk of CVD and T2D. In fact, an estimated 90% patients with T2D are obese.5,6

Despite a multifactorial management approach treating patients with the best CV and T2D standards of care, there is still a residual risk of CV events. The Treating to New Targets (TNT) study randomized 1501 patients with diabetes and coronary heart disease (CHD) to receive either atorvastatin 10 mg or 80 mg daily, and found that 18% to 14% of patients still experienced a major adverse CV event.7

The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial produced results that led to the approval of Victoza® as a T2D medication to reduce the risk of major adverse CV events (CV death, non-fatal MI, or non-fatal stroke) in patients with T2D and established CVD.2 LEADER included 9340 adult patients with T2D who had a glycated hemoglobin (A1C) level of ≥7%; these patients were randomized in a 1:1 ratio to receive either 1.8 mg Victoza® (or maximum tolerated dose) or matching placebo both in addition to standard CV risk-reducing therapy and antidiabetic therapy.8

The study was prospectively designed to evaluate noninferiority and subsequent superiority of CV event occurrence in patients taking Victoza® versus placebo. Enrolled patients were either 50 years or older with at least 1 CV coexisting condition or CKD, or 60 years or older with at least 1 CV risk factor. In the time-to-event analysis, the primary composite endpoint was the first occurrence of a major adverse cardiovascular event (MACE) comprised of a CV-related death, nonfatal myocardial infarction, or nonfatal stroke.8

Victoza® significantly reduced the risk of a major adverse cardiovascular event (MACE) with a relative risk reduction (RRR) of 13% and absolute risk reduction (ARR) of 1.9% when compared to placebo (HR 0.87; 95% CI, 0.78-0.97; P = .01). As a prespecified secondary endpoint, Victoza® also provided a significant life-saving benefit with an RRR of 22% and an ARR of 1.3% for CV death (HR 0.78; 95% CI, 0.66-0.93); see FIGURE 1 and FIGURE 28 for study results. Additionally, as a prespecified secondary endpoint, Victoza® was associated with an RRR of 15% and an ARR of 1.4% for all-cause mortality when compared with placebo (HR 0.85; 95% CI, 0.74-0.97).8

As of August 25, 2017, the indication for Victoza® has been updated to reflect the results of the LEADER trial. As of this writing, Victoza® is the only T2D treatment approved to reduce the risk of major adverse cardiovascular events (MACE), which consists of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, in adults with T2D and established CVD. Notably, the prescribing information update also removed the limitation for first-line use of Victoza®.2

Similarly, diabetes treatment guidelines committees have updated their recommendations accordingly. The American Diabetes Association’s (ADA) 2017 standards of care guidelines have listed Victoza® as a recommended treatment to reduce the risk of CV-related mortality, and recommend that the treatment be considered for patients with long-standing suboptimally controlled T2D and established ASCVD.1

Across multiple head-to-head trials against other antidiabetic medications, Victoza® is unsurpassed in A1C and weight loss reductions.9-11 Within 52 weeks, Victoza® has demonstrated A1C reductions as high as 1.5% with additional benefit of weight loss of up to 8.1 pounds.12 After a 26-week trial versus Trulicity (dulaglutide), Victoza® demonstrated greater weight loss of 7.9 pounds when compared to 6.4 pounds with Trulicity.10 Victoza® is not indicated for chronic weight management and weight change was a secondary endpoint in clinical trials.

Pharmacists often face concerns regarding product costs, but may be able to resolve cost concerns by introducing medications that have broad formulary coverage, such as Victoza®, which is covered by the majority of health plans nationwide. Within the GLP-1 RA class, Victoza® offers the lowest brand co-pay coverage.13 By helping patients and health care providers navigate information, pharmacists can make meaningful differences in a patient’s health and facilitate better quality of care. Victoza® offers savings programs such as the Victoza® instant savings card, where eligible patients can pay as little as $25 per month (maximum savings of $100) for their Victoza® prescription for up to 24 months. Patients with a savings card who enroll in VictozaCareTM may also be eligible to receive a free box of NovoFine 32G Tip needles.14 Victoza® benefits from broad formulary coverage and is available on the majority of health plans nationwide.15 To check the formulary status for your local plans, go to

VictozaCareTM is a free program that provides patient support with live coaching from a Certified Diabetes Educator (CDE) and access to Cornerstones4Care® tools. The VictozaCareTM Patient Starter Kit offers voice-over instructions on pen administration, co-pay information, and a quick-start guide for patients new to Victoza®. Patients enrolled in VictozaCareTM were found to be more adherent than those patients who were not, and filled approximately 1.2 more Victoza® prescriptions per year.

An estimated one-third (31.3%) of prescriptions written by physicians are never filled.16 As one of the most trusted professionals, pharmacists are uniquely positioned to communicate the importance of medication adherence and may be involved in discussing alternatives when a product is discontinued, not covered by insurance, or not preferred by the patient.17

Reducing CV events in patients with diabetes is an important clinical priority, as these events greatly impact diabetic morbidity and mortality. To optimize diabetic care, both patients and pharmacists can focus on multifactorial lifestyle management approaches which include nutrition education, weight management through physical activity, and mental health care.1 Pharmacists can assist their adult patients with T2D and established CVD by discussing agents that have demonstrated CV event reductions from robust clinical trials. Considering the favorable CV results that Victoza® displayed in the LEADER trial, Victoza® may play a role in treatment plans for patients with T2D and established CVD.8

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 diabetic ketoacidosis. Concurrent use with prandial insulin has not been studied.

Victoza® is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with a prior serious hypersensitivity reaction to Victoza® or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with Victoza®.

Warnings and Precautions
Patients should be referred to an endocrinologist for further evaluation if serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging.

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with Victoza® postmarketing. Observe patients carefully for signs and symptoms of pancreatitis (persistent severe abdominal pain, 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®.

Pen-sharing poses a risk for transmission of blood-borne pathogens.

When Victoza® is used with an insulin secretagogue (eg, a sulfonylurea) or insulin, serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis, have been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration. Use caution when initiating or escalating doses of Victoza® in patients with renal impairment.

Serious hypersensitivity reactions (eg, anaphylaxis 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®.

In the LEADER trial, 3.1% of Victoza® vs. 1.9% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. The majority of events required hospitalization or cholecystectomy. If cholelithiasis is suspected, gallbladder
studies and appropriate clinical follow up are indicated.

The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are nausea, diarrhea, headache, vomiting, decreased appetite, dyspepsia, and constipation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

Victoza® causes a delay of gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with Victoza®.

Victoza® has not been studied in patients with type 2 diabetes below 18 years of age and is not recommended for use in pediatric patients. Victoza® slows gastric emptying. Victoza® has not been studied in patients with pre-existing gastroparesis.
Victoza® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In 5 placebo-controlled clinical trials of at least 26 weeks’ duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 Victoza®-treated patients (7.5 events per 1000 patientyears). Of these 8 Victoza®-treated patients, 7 patients were concomitantly using a sulfonylurea.

In the pool of 5 placebo-controlled clinical trials, withdrawals due to gastrointestinal adverse reactions occurred in 4.3% of Victoza®- treated patients and 0.5% of placebo-treated patients. Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials.

Please see full , including , and .

  1. American Diabetes Association. Standards of medical care in diabetes-2017. Diabetes Care. 2017;40(supp 1).
  2. Victoza [prescribing information]. Plainsboro, NJ: Novo Nordisk, Inc; 2017.
  3. Low Wang CC, Hess CN, Hiatt WR, et al. 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. doi: 10.1161/CIRCULATIONAHA.116.022194.
  4. Kern DM, Devore S, Kim J, et al. Mortality, outcomes, and healthcare costs in T2DM patients at risk for cardiovascular disease. Am J Accountable Care. 2015;44(9):1118-1120.
  5. World Health Organization. Obesity and overweight fact sheet. WHO website. Accessed September 7, 2017.
  6. Leon BM, Maddox TM. Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes. 2015;6(13):1246-1258. doi: 10.4239/wjd.v6.i13.1246.
  7. 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. Diabetes Care. 2006;29(6):1220-1226. doi: 10.2337/dc05-2465.
  8. Marso SP, Gilbet DH, 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. doi: 10.1056/NEJMoa1603827.
  9. Pratley RE, Nauck MA, Barnett AH, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2():289-297. S2213-8587(13)70214-6.
  10. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384:1349-1357. S0140-6736(14)60976-4.
  11. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381:117-124. S0140-6736(12)61267-7.
  12. Pratley R, 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. doi: 10.1111/j.1742-1241.2011.02656.x.
  13. Data from VANTAGE FingerTip Formulary bridge/May 2017. Nomenclature and Xponent PlanTrak using week ending 6/02/2017. Only considers bridged volume; excludes cash and mail order data; based on full DCS/EDCS/IDCS/HSDCS IC universe (Targets + Non-Targets).
  14. Novo Nordisk. Get More Information. Victoza website. Accessed October 2, 2017.
  15. Formulary data are provided by FingerTip Formulary and are current as of October 2017.
  16. Tamblyn R, Eguale T, Huang A, et al. The incidence and determinants of primary nonadherence with prescribed medication in primary care. Ann Intern Med. 2014;160:441-550. doi: 10.7326/M13-1705.
  17. Tarn DM, Paterniti DA, Wenger NS, et al. Older patient, physician, and pharmacist perspectives about community pharmacists' roles. Int J Pharm Pract. 2012;20(5):285-293. doi:10.1111/j.2042-7174.2012.00202.x.

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