By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a third long-acting basal human insulin analog. Insulin degludec differs from human insulin at position B30, where threonine has been replaced with a side chain consisting of glutamic acid and a C16 fatty acid, which results in an ultra-long duration of action (> 40 hours). Researchers produce it with recombinant technology using yeast cells. It is marketed by Novo Nordisk as Tresiba.
INDICATIONS
Insulin degludec is indicated for use as a long-acting insulin to improve glycemic control in adults with diabetes mellitus.1
DOSAGE
Insulin degludec is given subcutaneously once daily and the dose is individualized. It is available as 100 units/mL and 200 units/mL at 3 mL in prefilled pens (FlexTouch). It also will be available in combination with insulin aspart in a 70/30 ratio (Ryzodeg) in other parts of the world and perhaps eventually in the United States.
POTENTIAL ADVANTAGES
Insulin degludec provides an alternative to insulin glargine and insulin detemir as long-acting human insulin analogs. It may be administered at different times of the day without loss of efficacy.
POTENTIAL DISADVANTAGES
Increase in body weight was greater with insulin degludec compared to insulin detemir.3
COMMENTS
Insulin degludec forms a stable depot of multi-hexamers upon injection.2 There is a gradual dissociation of these hexamers into readily absorbed monomers. Three studies evaluated the efficacy of insulin degludec in type 1 diabetic subjects and in six studies in type 2 diabetic subjects.1 In type 1 subjects, insulin degludec was compared to insulin glargine and insulin detemir using a noninferiority design with a pre-specified noninferiority margin of 0.4%. In type 2 subjects, insulin degludec was compared to insulin glargine when added to oral antidiabetic agents and, in one study, compared to sitagliptin when added to oral agents. In two 52-week studies in type 1 diabetics, insulin degludec was noninferior to insulin glargine and insulin detemir when administered with the evening meal and insulin aspart administered before each meal. The difference in HbA1c reduction from baseline compared to insulin glargine was -0.01% (95% confidence interval [CI], -0.14% to 0.11%). The difference compared to insulin detemir was -0.09% (95% CI, -0.23% to 0.05%).
In a 26-week study, insulin degludec, when administered any time each day, was also noninferior compared to insulin glargine administered at the main evening meal. Type 2 insulin-naïve diabetics who were inadequately controlled on one or more oral agents were randomized to insulin degludec or insulin glargine. At week 52, noninferiority was shown with a treatment difference of -0.09% (95% CI, -0.04 to 0.22). In subjects who were inadequately controlled on various insulin regimens, oral agents, or any combination, noninferiority was shown for insulin degludec and insulin glargine. The results were similar when administering insulin degludec at alternate times.
In a 26-week study, insulin degludec was noninferior to insulin glargine when added to metformin with or without a DPP-4 inhibitor. Insulin degludec, plus one or more oral agents, was superior to add-on sitagliptin. In type 1 subjects, the overall rate of confirmed hypoglycemia and severe hypoglycemia was not significantly different between insulin degludec and detemir.3 However, the rate of nocturnal confirmed hypoglycemia was lower with insulin degludec. Similarly, the rates of nocturnal confirmed hypoglycemia were numerically or significantly lower with insulin degludec compared to insulin glargine.4
CLINICAL IMPLICATIONS
Insulin degludec is noninferior to insulin glargine and insulin detemir in terms of glycemic control but may offer a lower risk of nocturnal hypoglycemia. The clinical relevance remains to be determined as the absolute difference, while statistically significant in some studies, is quite low — about 1.5 episodes per patient years of exposure for type 1 subjects and 0.4 for type 2 subjects.4,5 Insulin degludec is slightly more expensive — $29.60 per 100 units for insulin degludec compared to $26.90 for insulin detemir and $24.90 for insulin glargine. Insulin degludec is expected to be available in the first quarter of 2016.
REFERENCES
- Tresiba Prescribing Information. Novo Nordisk. September 2015.
- Vora J, et al. Clinical use of insulin degludec. Diabetes Res Clin Pract 2015;109:19-31.
- Davies M, et al. Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial. Diabetes Obes Metab 2015 Sep 7. doi: 10.1111/dom.12573. [Epub ahead of print].
- Russell-Jones D, et al. Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma glucose vs. insulin glargine: A meta-analysis of seven clinical trials. Nutr Metab Cardiovasc 2015;25:898-905.
- Garber AJ, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): A phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet2012;379:1498-1507.