Tibin K. Titus, Mercer University College of Pharmacy
Type 2 diabetes affects millions of people worldwide.  Among the complications that arise from diabetes are cardiovascular (CV) complications such as stroke, coronary heart disease, and vascular disease.  Additionally, studies have shown that type 2 diabetics who require insulin have increased rates of cardiovascular events. [2,3]
Degludec is a new and ultra long acting basal insulin that came into the market in 2016. It is approved for glycemic control in type 2 diabetes. The Food and Drug Administration (FDA) requires all new diabetes drugs to have a CV risk study.  To fill the gap in knowledge for the CV safety of degludec, the following study was conducted. 
|Efficacy and safety of degludec versus glargine in type 2 diabetes|
|Design||Randomized, double blinded, treated-to-target, event driven cardiovascular outcomes, noninferiority trial; N=7,637|
|Objective||To investigate the efficacy and safety of degludec compared to glargine, specifically cardiovascular safety of degludec, in patients that are type 2 diabetics|
|Study Groups||Insulin degludec (n=3,818); Insulin glargine U100 (n=3,819)|
|Methods||Patients were randomly assigned in a 1:1 ratio to receive degludec or glargine (10ml vial/100U per mL). Patients administered insulin once daily between dinner and bedtime. Patients were seen weekly for 2 weeks, monthly for 6 months, and then every 3 months for the remaining part of the trial. A prespecified noninferiority margin of 1.3.
Inclusion criteria: Age > 50 years predefined previous cardiovascular disease or renal disease, or age ≥60 years with predefined cardiovascular risk factors, treated with at least one or more oral or injectable antihyperglycemic agents, A1c >7%, if < 7% then had to be treated with >20 units basal insulin/day
Exclusion criteria: Acute coronary or CV event in last 60 days, CHF NYHA Class IV, current or past malignant neoplasms
|Duration||November 2013 – November 2014|
|Primary Outcome Measure||CV death, nonfatal myocardial infarction, or nonfatal stroke|
The primary composite outcome was analyzed with the use of a Cox proportional-hazards regression model with treatment group as a factor in the intention-to-treat population with testing for noninferiority. All p values are two-sided unless otherwise stated.
† This one-sided p value confirmed noninferiority. The two-sided p value testing for a significant between-group difference was 0.21.
‡ The expanded composite cardiovascular outcome (a secondary outcome) consisted of the primary composite outcome plus unstable angina leading to hospitalization.
The number of severe hypoglycemic episodes was tested for superiority with the use of a negative binomial-regression model adjusted for observation time as offset (100 patient-years) and treatment group, and the incidence was tested with the use of a logistic-regression model adjusted for treatment group. All p values are two-sided unless otherwise stated.
† This one-sided p value confirmed superiority.
‡ This comparison was calculated as an odds ratio.
|Adverse Events||Common Adverse Events: nocturnal severe hypoglycemia (4.9% degludec vs. 6.6% glargine)|
|Serious Adverse Events: non-fatal myocardial infraction (3.8% degludec vs. 4.4% glargine), non-fatal stroke (1.9% degludec vs. 2.1% glargine), neoplasms (3.2% degludec vs. 3.0% glargine)|
|Percentage that Discontinued due to Adverse Events: N/A|
|Study Author Conclusions||The results show that degludec is similar to insulin glargine in improving glycemic control and noninferior for reducing cardiovascular events in patients with type 2 diabetes and high cardiovascular risk. This trial thus establishes the cardiovascular safety profile of degludec for use in patients with type 2 diabetes, compared with insulin glargine.|
The study was well designed with a large sample size leading to high internal and external validity. However, only 25% of the population was non-white. This may be a limitation as African-Americans are at a higher CV risks and diabetes.  Whether including higher percentage of such population would have resulted in different outcomes is unclear. Moreover, having a higher percentage of African-American patients may have been a better reflection of the population that may benefit the most from the cardiovascular effects of degludec.
The study had a composite primary endpoint; however, as the results show no differences in individual component outcomes, it may be reasonable to conclude that the overall noninferiority was not driven by certain outcomes of the composite endpoint. Given the long half-life of the drug, degludec is another once-daily option for patients seeking more convenient regimen. Moreover, the study suggests it is associated with lower rates of severe hypoglycemia. Although it may be relatively expensive compared to glargine, degludec may be a viable option for patients with previous history of severe hypoglycemia or nocturnal hypoglycemia while on optimal dose of glargine.
- Centers for Disease Control and Prevention. Diabetes Epidemiology http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed January 10, 2018.
- Munnee K, Bundhun PK, Quan H, Tang Z. Comparing the clinical outcomes between insulin-treated and non-insulin treated patients with type 2 diabetes mellitus after coronary artery bypass surgery: a systematic review and meta-analysis. Medicine (Baltimore). 2016;95(10):30-36.
- Li J, Tong Y, Zhang Y, et al. Effects on all-cause mortality and cardiovascular outcomes in patients with type 2 diabetes by comparing insulin with oral hypoglycemic agent therapy: a meta-analysis of randomized controlled trials. Clin Ther. 2016;38(2):372-386.
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- Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk & Co; December 2016.
- US. Food and Drug Administration. Diabetes Mellitus Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Washington, DC: U.S Department of Health and Human Services; December 2008.
- Marso SP, McGuire DK, Zinman B, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377(8):723-732.
- Centers for Disease Control and Prevention. Diabetes Epidemiology https://www.cdc.gov/diabetes/basics/risk-factors.html Accessed January 10, 2018.